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Dasatinib In Combination With Weekly Paclitaxel For Patients With Metastatic Breast Carcinoma CA 180 194
This study is currently recruiting participants.
Verified by Memorial Sloan-Kettering Cancer Center, January 2009
Sponsors and Collaborators: Memorial Sloan-Kettering Cancer Center
Bristol-Myers Squibb
Baylor College of Medicine
Information provided by: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00820170
  Purpose

The purpose of this study is to find the highest dose of dasatinib that can be safely given to a patient when the drug is given in combination with the known anticancer drug paclitaxel. Paclitaxel is an established anti-cancer drug, used in the treatment of many cancers, and it is an approved treatment for breast cancer. Dasatinib has been approved by the Food and Drug Administration for use as a single therapy in another kind of cancer, but its use in breast cancer patients, and in combination with paclitaxel is investigational.

In this study, we will test the safety of dasatinib when given at different dose levels in combination with paclitaxel. We want to find out what effects, good and/or bad, it has on the patient and on metastatic breast cancer.


Condition Intervention Phase
Breast Cancer
Drug: Dasatinib and Paclitaxel
Phase I
Phase II

Genetics Home Reference related topics: breast cancer
MedlinePlus related topics: Breast Cancer Cancer
Drug Information available for: Paclitaxel Dasatinib
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment, Open Label, Single Group Assignment, Safety/Efficacy Study
Official Title: A Phase I-II Study of Dasatinib in Combination With Weekly Paclitaxel for Patients With Metastatic Breast Carcinoma

Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • Phase I Portion: To determine the MTD of dasatinib when administered in combination with a fixed dose of weekly paclitaxel. [ Time Frame: conclusion of the phase I portion of the study ] [ Designated as safety issue: Yes ]
  • Phase II Portion: To estimate efficacy (objective response rate; ORR; complete response (CR) + partial response (PR)) of dasatinib when administered in combination with weekly paclitaxel at the MTD established during the phase I portion of this trial. [ Time Frame: conclusion of the study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Phase I Portion: To obtain preliminary data on the therapeutic activity of dasatinib when administered in combination with weekly paclitaxel. [ Time Frame: conclusion of the phase I portion of the study ] [ Designated as safety issue: No ]
  • Phase II Portion: To obtain safety and tolerability of dasatinib when administered in combination with weekly paclitaxel. [ Time Frame: conclusion of the study ] [ Designated as safety issue: Yes ]
  • Phase II: To estimate secondary efficacy endpoints of this combination including clinical benefit (CR+PR+SD > 6 months), time to tumor progression (TTP), progression free survival (PFS) and duration of response. [ Time Frame: conclusion of the study ] [ Designated as safety issue: No ]
  • Phase II: To obtain exploratory tumor biomarker data: assays of p-SRC, VEGFR2 and Collagen Type IV in plasma, obtained at baseline and after 2 cycles of treatment (8 weeks), will be performed by enzyme-linked immunosorbent assay. [ Time Frame: conclusion of the study ] [ Designated as safety issue: No ]
  • Phase II: To perform analysis of mRNA expression on the tumor specimens, for a gene expression profiling of the responders versus non-responders, in order to identify potential predictors of response to dasatinib. [ Time Frame: conclusion of the study ] [ Designated as safety issue: No ]
  • Phase II: To collect circulating tumor cells (CTC) at baseline and after 2 cycles of treatment (8 weeks) [ Time Frame: conclusion of the study ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: January 2009
Estimated Study Completion Date: January 2013
Estimated Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
dasatinib and paclitaxel: Experimental

The phase I portion is a standard, three-patient per cohort, dose escalation schedule will be used. Between 6 and 54 patients will likely be necessary to determine the MTD of dasatinib in combination with weekly paclitaxel.

The phase II portion of this trial has a Simon two-stage design to determine the efficacy of dasatinib when administered in combination with paclitaxel.

Drug: Dasatinib and Paclitaxel

A treatment cycle will consist of 28 days, according to the following schedule:

Dasatinib PO once daily, Weekly paclitaxel 80 mg/m2 given intravenously over 1 hour on day 1, 8, and 15 of a 28 day cycle.

The trial will initially test the combination of weekly paclitaxel and dasatinib given PO, once daily , continuously. In case of 2 dose-limiting toxicities (DLT) in the first cohort (0), the next cohort will test dasatinib given with a different schedule, 5 days on and 2 days off, omitting dasatinib the day prior and the day of administration of paclitaxel.


  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Female or male patients with diagnosis of invasive adenocarcinoma of the breast confirmed at MSKCC or at Baylor College of Medicine by histology.
  • For the phase I portion, patients with any ER/PR/HER2 disease status, no longer eligible for hormonal therapy or HER2-targeted therapy, will be eligible.
  • For the phase II portion, there needs to be documentation of negative HER2 (IHC 0-1+ or FISH/CISH negative) status. Patients with any ER/PR disease status are eligible.
  • A paraffin-embedded tissue block or unstained slides from prior surgery must be available.
  • Evidence of recurrent or progressive locally advanced or metastatic breast cancer.

Presence of:

  • For the phase I portion: at least one evaluable or measurable metastatic lesion ,
  • For the phase II portion: at least one measurable metastatic lesion according to the RECIST criteria which has not been irradiated (i.e. newly arising lesions in previously irradiated areas are accepted).Ascites, pleural effusion, and bone metastases are not considered measurable. Minimum indicator lesion size: > or = to 10 mm measured by spiral CT or > or = to 20 mm measured by conventional techniques.

Prior therapies:

For the phase I portion: Any number of prior endocrine or biologic therapies is permitted . In addition, patients may be untreated in the metastatic setting or have received any number of prior cytotoxic regimens.

For the phase II portion: 0-2 prior therapies for metastatic disease are allowed.

Prior taxane therapy, either in the adjuvant or in the metastatic setting, either deliver weekly, q 2 weeks or q 3 weeks, will be permitted. Prior therapy with bevacizumab will be allowed. All previous chemotherapy, radiotherapy and intravenous bisphosphonates must have been discontinued at least 3 weeks prior to study entry, 3 weeks also for trastuzumab and bevacizumab. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to NCI CTC (Version 3) Grade ≤1.

  • Endocrine therapy with an aromatase inhibitor, SERM (ie, tamoxifen) or fulvestrant is permitted, however it must be discontinued before enrolling in the study.
  • ECOG performance status of 0 or 1.
  • Age > or = to 18 years old. Adequate Organ Function
  • Total bilirubin ≤ 1.5 times the institutional Upper Limit of Normal (ULN)
  • Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN
  • Serum Na, K+, Mg2+, Phosphate and Ca2+≥ Lower Limit of Normal (LLN)
  • Serum Creatinine ≤ 1.5 time the institutional ULN
  • Neutrophil count, Platelets, PT, PTT all Grade 0-1
  • Ability to take oral medication (dasatinib must be swallowed whole)

Concomitant Medications:

  • Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy
  • Patient agrees that IV bisphophonates will bewithheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia. Concomitant Medications, any of the following should be considered for exclusion:

Category I 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) such as:

  • quinidine, procainamide, disopyramide
  • amiodarone, sotalol, ibutilide, dofetilide
  • erythromycin, clarithromycin
  • chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
  • cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
  • 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. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of dasatinib.
  • Patient may not be receiving any prohibited CYP3A4 inhibitors.

Women of childbearing potential (WOCBP) must have:

  • A negative serum or urine pregnancy test 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
  • Pregnant or nursing women may not participate. Patients of reproductive potential may not participate unless they have agreed to use an effective method of contraception and to continue contraception for 30 days from the date of the last study drug administration. Postmenopausal woman must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
  • Signed written informed consent including a HIPAA form according to institutional guidelines.

Exclusion Criteria:

  • Life expectancy < 3 months.
  • Prior severe allergic reaction to paclitaxel therapy.
  • Presence of new or recurrent and symptomatic pleural effusion (NCI CTC Grade 2, 3 or 4).
  • Completion of previous chemotherapy regimen < 3 weeks prior to the start of study treatment.
  • Prior hormonal therapy must be discontinued prior to treatment start. Biologic therapy (eg, bevacizumab, trastuzumab) for the treatment of metastatic disease must be discontinued > or = to 3 weeks from the start of protocol treatment.

Concurrent medical condition which may increase the risk of toxicity, including:

  • Pleural or pericardial effusion of any grade; however, patients with only blunting of the costo-phrenic angle will be eligible; patients with a treated pleural effusion, i.e. s/p pleurodesis, will be eligible if no residual pleural effusion is evident;

Cardiac Symptoms; any of the following should be considered for exclusion:

  • Uncontrolled angina, congestive heart failure or MI within (6 months)
  • Diagnosed congenital long QT syndrome
  • Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
  • Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration

History of significant bleeding disorder unrelated to cancer, including:

Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

  • Diagnosed acquired bleeding disorder within one year (e.g., acquired antifactor VIII antibodies)
  • Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding Other medical condition which in the opinion of the Investigator might confer an unacceptable increase in risk.
  • Patients with symptomatic CNS metastases that remain untreated by radiation therapy are excluded from this trial. The presence of asymptomatic brain metastases or brain metastases that have been previously irradiated are not grounds for trial exclusion.
  • History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake.
  • Presence of uncontrolled gastrointestinal malabsorption syndrome.
  • Unwillingness to give written informed consent or unwillingness to participate or inability to comply with the protocol for the duration of the study. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures are necessary for participation in this clinical trial.
  • Concurrent radiotherapy is not permitted for disease progression on treatment on protocol, but might allowed for pre-existing non-target lesions with approval from the principal investigator of the trial.
  • Patients with > Grade 1 neuropathy will be excluded form this trial.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00820170

Contacts
Contact: Monica Fornier, MD 212 629-5240
Contact: Clifford Hudis, MD 212-639-5449

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Monica Fornier, MD     212-629-5240        
Contact: Clifford Hudis, MD     212-639-5449        
Principal Investigator: Monica Fornier, MD            
United States, Texas
Baylor College of Medicine Not yet recruiting
Houston, Texas, United States, 77005
Contact: Jenny Chang, MD            
Principal Investigator: Jenny Chang, MD            
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Bristol-Myers Squibb
Baylor College of Medicine
Investigators
Principal Investigator: Monica Fornier, MD Memorial Sloan-Kettering Cancer Center
  More Information

Memorial Sloan-Kettering Cancer Center  This link exits the ClinicalTrials.gov site

Responsible Party: Memorial Sloan-Kettering Cancer Center ( Monica Fornier, MD )
Study ID Numbers: 08-122
Study First Received: January 8, 2009
Last Updated: January 12, 2009
ClinicalTrials.gov Identifier: NCT00820170  
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
Breast
Cancer
DASATINIB
TAXOL (PACLITAXEL)

Study placed in the following topic categories:
Skin Diseases
Paclitaxel
Dasatinib
Breast Neoplasms
Breast Diseases
Carcinoma

Additional relevant MeSH terms:
Neoplasms
Neoplasms by Site
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Therapeutic Uses
Mitosis Modulators
Tubulin Modulators
Enzyme Inhibitors
Antimitotic Agents
Protein Kinase Inhibitors
Antineoplastic Agents, Phytogenic
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 16, 2009