Dasatinib In Combination With Weekly Paclitaxel For Patients With Metastatic Breast Carcinoma CA 180 194

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT00820170
First received: January 8, 2009
Last updated: May 19, 2014
Last verified: May 2014
  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 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I-II Study of Dasatinib in Combination With Weekly Paclitaxel for Patients With Metastatic Breast Carcinoma

Resource links provided by NLM:


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 ]
  • Phase II: Exploratory somatic gene mutations detection in archived tumor samples [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: January 2009
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: dasatinib and paclitaxel

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 120MG 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.
  • 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 biphosphonates 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, both Grade 0-1
  • PT (INR) and PTT Grade 0-1, except for patients on Coumadin or low molecular weight heparin
  • 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 biphosphonates will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia. Concomitant Medications, any of the following should be considered for exclusion:

Patient agrees to discontinue QT-prolonging agents strongly associated with 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 potent CYP3A4 inhibitors. These are prohibited (patients must discontinue drug ≥7 days prior to starting dasatinib) and include:
  • itraconazole, ketoconazole, miconazole, coriconazole
  • amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir
  • ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin, imatinib, isoniazid
  • ketamine, nefazodone, nicardipine, propofol, quinidine, telithromycin

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 pleural effusion which is symptomatic and/or requiring medical intervention (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.

Patients may not have any clinically significant cardiovascular disease including the following:

  • myocardial infarction or ventricular tachyarrhythmia within 6 months
  • prolonged QTc >480 msec (Fridericia correction)
  • ejection fraction less than institutional normal
  • major conduction abnormality (unless a cardiac pacemaker is present)
  • Patients with any cardiopulmonary symptoms of unknown cause (e.g. shortness of breath, chest pain, etc.) should be evaluated by a baseline echocardiogram with or without stress test as needed in addition to electrocardiogram (EKG) to rule out QTc prolongation. The patient may be referred to a cardiologist at the discretion of the principal investigator. Patients with underlying cardiopulmonary dysfunction should be excluded from the study.
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00820170

Contacts
Contact: Monica Fornier, MD 646-888-5240
Contact: Clifford Hudis, MD 646-888-5449

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Monica Fornier, MD    646-888-5240      
Contact: Clifford Hudis, MD    646-888-5449      
Principal Investigator: Monica Fornier, MD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Bristol-Myers Squibb
Investigators
Principal Investigator: Monica Fornier, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00820170     History of Changes
Other Study ID Numbers: 08-122
Study First Received: January 8, 2009
Last Updated: May 19, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
Breast
Cancer
DASATINIB
TAXOL (PACLITAXEL)
08-122

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Paclitaxel
Dasatinib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014