Dasatinib in Resectable Malignant Pleural Mesothelioma - Full Text View

Sponsor:	M.D. Anderson Cancer Center
Collaborators:	Bristol-Myers Squibb Department of Defense
Information provided by:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT00652574

Purpose

The primary objective of this novel phase I trial will be the level of biomarker modulation of p-Src Tyr 419 by induction dasatinib therapy in patients with resectable malignant pleural mesothelioma.

Secondary objectives include overall and progression-free survival, tumor radiographic and pathologic response, and safety-toxicity profiles. Exploratory analyses will include additional biomarker evaluation in pre- and post-treatment tumor specimens, and serum/platelet/pleural effusion biomarker modulation.

Condition	Intervention	Phase
Malignant Pleural Mesothelioma	Drug: Dasatinib	Phase I

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title:	Phase I Trial of Induction Dasatinib Therapy in Patients With Resectable Malignant Pleural Mesothelioma

Resource links provided by NLM:

MedlinePlus related topics: Cancer Mesothelioma

Drug Information available for: Dasatinib

U.S. FDA Resources

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

Primary Outcome Measures:

Modulation of biomarker p-Src Tyr419 expression [ Time Frame: Days 7, 14, 21, and 28 of treatment followed by 5-6 core biopsies during surgery. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Overall and progression-free survival times [ Time Frame: 2 Years ] [ Designated as safety issue: No ]

Estimated Enrollment:	24
Study Start Date:	March 2008
Estimated Primary Completion Date:	March 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Dasatinib: Experimental Dasatinib = BMS-354825, Sprycel	Drug: Dasatinib 70 mg by mouth twice daily x 28 days, for up to 2 years after surgery.

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Detailed Description:

THE STUDY DRUG:

DASATINIB is designed to decrease the activity of one or more proteins that are responsible for the uncontrolled growth of tumor cells. This may cause the tumor cells to die.

SCREENING TESTS:

Before you can start taking the study drug, you will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests and procedures will be performed:

Your complete medical history will be recorded.
You will have a physical exam, including measurement of vital signs (temperature, blood pressure, pulse, and breathing rate) and weight. You will also have a test to check the amount of oxygen in your blood.
Blood (about 3-4 teaspoons) will be drawn for routine tests.
You will be asked how well you are able to perform the normal activities of daily living (performance status evaluation).
You will have an electrocardiogram (ECG--a test that measures the electrical activity of the heart).
Blood (about 1-2 teaspoons) will be drawn to check how well your blood clots.
You will have a positron emission tomography (PET) scan to check the status of the disease.
Women who are able to have children must have a negative blood (about 1-2 teaspoons) or urine pregnancy test.

Before you begin taking dasatinib, you will also be tested to check the status of the disease and to help the doctor decide which type of surgery you will have. You will have a laparoscopy, mediastinoscopy, bronchoscopy, and either a video-assisted thoracoscopy or intraoperative ultrasound-guided core biopsy. You will be given a separate consent for each of these procedures, which will describe the procedures and any risks in detail.

Laparoscopy is a surgical procedure that uses a thin, lighted tube put through a cut (incision) in the belly to look at the abdominal organs or the female pelvic organs.

Mediastinoscopy is a surgical procedure to examine the inside of the upper chest between and in front of the lungs (mediastinum). During a mediastinoscopy, a small incision is made in the neck just above the breastbone or on the left side of the chest next to the breastbone. Then a thin scope (mediastinoscope) is inserted through the opening. A tissue sample (biopsy) can be collected through the mediastinoscope and then examined under a microscope for lung problems, such as infection, inflammation, or cancer.

Video-assisted thoracoscopy (VATS) is a procedure to take a biopsy of lung tissue through a small incision between two ribs with the aid of a thin, lighted tube (videoscope) and small surgical instruments.

For the intraoperative ultrasound-guided core biopsy of the lung, subcutaneous, and/or lymph node biopsy, a tissue sample is withdrawn from an organ or suspected tumor mass using a very thin needle and a syringe. The needle is guided while being viewed by the physician on a computed tomography (CT) scan. Any site that can be safely biopsied will be considered for the collection of tissue.

For a bronchoscopy, you will be given drugs to relax, and then a local anesthetic will be sprayed into your nose and throat to numb those areas. A slim, flexible tube with a light will be placed through your nose or mouth and into your lungs. A small brush will be fed through the tube and into your lungs. The brush will gently scrape off a sample of lung tissue. Tweezers will then be fed through the tube to collect the tissue samples. A small amount of water will be sprayed into your lungs and then suctioned out through the tube to collect additional tissue samples.

STUDY DRUG ADMINISTRATION:

If you are found to be eligible to take part in this study, you will take 2 dasatinib tablets by mouth 2 times a day for the 4 weeks before surgery (in the morning and 12 hours later). Dasatinib may be taken with or without food, but should be swallowed with at least 1 cup (8 ounces) of water. A light meal is not required, but may help you avoid getting a stomach ache when you take your dose. Tablets must be swallowed whole and may not be broken. If vomiting occurs within 30 minutes of swallowing the tablet(s), you can take another dose. If you miss a dose of dasatinib, take it as soon as you remember on the same day. If you miss taking your dose for 12 hours, take your regular dose the next scheduled day (do not take double your regular dose to make up for the missed dose). You will be given a "pill diary" to write down when you take the study drug. You will be shown how to fill it out and asked to bring the diary with you to each clinic visit.

STUDY VISITS:

On Days 7, 14, 21, and 28, the following tests and procedures will be performed:

You will have a physical exam, including measurement of vital signs and weight.
You will also have a test to check the amount of oxygen in your blood.
Blood (about 3-4 teaspoons) will be drawn for routine tests.
You will have a performance status evaluation.
You will have an ECG.
Blood (about 1-2 teaspoons) will be drawn to check your how well your blood clots.

You will have a PET scan to check the status of the disease. This PET scan will be before your surgery, the study doctor will tell you when this will be performed.

SURGERY:

After you have taken dasatinib for 28 days, you will have surgery to remove the tumor. You will continue to take the dasatinib until midnight the night before the surgery. Depending on the status of the disease, you will have either a pleurectomy or extrapleural pneumonectomy. You will be given a separate consent for these procedures, which will describe the surgery and any risks in detail.

Pleurectomy is the surgical procedure to remove the parietal pleura (the outermost lining around the lungs).

An extrapleural pneumonectomy is a surgical procedure that removes portions of the lung, the parietal pleura (the lining of the lung), the pericardium (the lining of the heart), and the diaphragm.

During surgery, 5-6 core biopsies, if possible, will be taken from different areas of the tumor for biomarker testing.

For the CT-guided core biopsy of the lung, a tissue sample is withdrawn from an organ or suspected tumor mass using a very thin needle and a syringe. The needle is guided while being viewed by the physician on a CT scan.

LENGTH OF STUDY:

After surgery, your doctor will decide the type of treatment you should receive for your condition. If the disease responded well to the 4 weeks of dasatinib, you may be eligible to continue taking dasatinib once a day starting 4-6 weeks after your surgery. The doctor may also decide that you can take dasatinib once a day starting 4-6 weeks after receiving radiation therapy. You may continue to take dasatinib as long as you are benefitting. You will be taken off study if intolerable side effects occur or the disease gets worse.

FOLLOW-UP VISITS:

If you continue to receive the study drug after surgery, you will have a physical exam and a PET scan every 8 weeks.

If you are taken off study for any reason, you will return to the clinic once a month for 3 months and every 3 months for 2 years, for the following tests and procedures:

You will have a physical exam, including measurement of vital signs.
Blood (about 1-2 teaspoons) will be drawn for routine tests.
You will have a PET/CT.

This is an investigational study. Dasatinib is an investigational agent and ongoing clinical trials are using this drug in malignant mesothelioma. However, these studies have only recently started, and there is no information so far that shows the drug is effective in malignant mesothelioma. Dasatinib is FDA approved and commercially available for the treatment of acute lymphoid and chronic myeloid leukemia.

However, its use in this research study is investigational. Up to 24 participants will take part in this study. All will be enrolled at M. D. Anderson.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients with potentially resectable malignant pleural mesothelioma, IMIG stage I-III
Subject, age >/= 18 years
Performance Status (ECOG) PS 0-1
No prior chemotherapy for mesothelioma within the last 3 years
No prior radiation to the area of primary disease. Radiation to chest wall port sites is acceptable.
No prior targeted biologic therapy (i.e. EGFR inhibitors, VEGF inhibitors) within the last 3 years
Adequate Organ Function: a) Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN), b) Hepatic enzymes (AST, ALT ) </= 2.5 times the institutional ULN, c) Serum Na, K+, Mg2+, Phosphate and Ca2+>/= Lower Limit of Normal (LLN), d) Serum Creatinine < 1.5 time the institutional ULN, e) Hemoglobin, Neutrophil count, Platelets, PT, PTT all Grade 0-1
Ability to take oral medication (dasatinib must be swallowed whole)
Women of childbearing potential (WOCBP) must have: A negative serum or urine pregnancy test (sensitivity </= 25IU HCG/L) within 72 hours prior to the start of study drug administration
Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped
Signed written informed consent including HIPAA according to institutional guidelines

Exclusion Criteria:

Malignancy [other than the one treated in this study] which required radiotherapy or systemic treatment within the past 3 years.
Prior therapies to be excluded: any prior chemotherapy or targeted biologic therapy for mesothelioma used within the last 3 years
Concurrent medical condition which may increase the risk of toxicity, including: a) Clinically-significant coagulation or platelet function disorder (e.g. known von Willebrand's disease) b) Any disease which requires persistent anticoagulation therapy (and the patient may not be taken off the anti-coagulation safely) with coumadin, factor Xa inhibitors, or heparin (low-molecular weight, standard)
Cardiac Symptoms, consider the following: a) Uncontrolled angina, congestive heart failure or MI within (6 months), b) Diagnosed congenital long QT syndrome: 1. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes), 2. Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec), 3. Subjects with hypokalemia or hypomagnesemia if it cannot be corrected
History of significant bleeding disorder unrelated to cancer, including: a) Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease), b) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies), c) Ongoing or recent (</= 3 months) significant gastrointestinal bleeding
Concomitant Medications, consider the following prohibitions: a) Drugs that are generally accepted to have a risk of causing Torsades de Pointes including: (Patients must discontinue drug 7 days prior to starting dasatinib): A) quinidine, procainamide, disopyramide, B) amiodarone, sotalol, ibutilide, dofetilide, C) erythromycin, clarithromycin, D) chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide E) cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine. F) moxifloxacin, levofloxacin
The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not recommended.The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy.a)Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy,b)Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia,c)Patient may not be receiving any prohibited CYP3A4 inhibitors,d)Patient may not be receiving any alternative herbal remedies during the dasatinib treatment period
Women: a) are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after cessation of study drug, or, b) have a positive pregnancy test at baseline, or c) are pregnant or breastfeeding, d) Sexually active women of childbearing potential (WOCBP) must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized.,
-continued from exclusion #8-: e) Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy., f) All WOCBP MUST have a negative pregnancy test prior to first receiving dasatinib. If the pregnancy test is positive, the patient must not receive dasatinib and must not be enrolled in the study.
Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00652574

Contacts

Contact: Anne S. Tsao, MD	713-792-6363
Contact: James Gil, RN	713-745-6766

Locations

United States, Texas
U.T.M.D. Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Anne S. Tsao, MD

Sponsors and Collaborators

M.D. Anderson Cancer Center

Bristol-Myers Squibb

Department of Defense

Investigators

Principal Investigator:

Anne S. Tsao, MD

U.T.M.D. Anderson Cancer Center

More Information

Additional Information:

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

No publications provided

Responsible Party:	U.T.M.D. Anderson Cancer Center ( Anne S. Tsao, MD/Assistant Professor )
Study ID Numbers:	2006-0935
Study First Received:	March 27, 2008
Last Updated:	June 30, 2009
ClinicalTrials.gov Identifier:	NCT00652574 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by M.D. Anderson Cancer Center:

Malignant Pleural Mesothelioma
Dasatinib
BMS-354825
Sprycel
MPM

Additional relevant MeSH terms:

Neoplasms
Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Neoplasms, Mesothelial
Dasatinib
Mesothelioma

Enzyme Inhibitors
Protein Kinase Inhibitors
Adenoma
Pharmacologic Actions
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on November 27, 2009