Dasatinib In Combination With Trastuzumab And Paclitaxel In The First Line Treatment Of Her2-Positive Metastatic Breast Cancer (MBC) Patients

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by Spanish Breast Cancer Research Group
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Spanish Breast Cancer Research Group
ClinicalTrials.gov Identifier:
NCT01306942
First received: February 24, 2011
Last updated: June 7, 2013
Last verified: June 2013
  Purpose

This is a single-arm, open-label, phase I/II study. In the phase I, patients with HER2-positive MBC will be treated with paclitaxel, trastuzumab and increasing doses of dasatinib to determine the MTD (Maximum Tolerated Dose), DLT (Dose Limiting Toxicity) and RPD (Recommended Phase II Dose) of the combination. Once the RPD has been identified, 48 additional patients will be treated at that dose to evaluate the efficacy and safety of the combination in the phase II.

Primary Objective:

  • To determine the maximum tolerated dose (MTD) and recommended phase II dose (RPD) of dasatinib in combination with fixed doses of trastuzumab and paclitaxel in HER2-positive MBC patients (Phase I).
  • To determine the efficacy, measured by objective response rate (ORR) in HER2-positive MBC patients with measurable disease (Phase II).

Primary Endpoint:

  • To determine the incidence rate of dose limiting toxicity (DLT) within the first cycle of dasatinib in combination with trastuzumab and paclitaxel at each dose level in HER2-positive MBC patients (Phase I).
  • To assess the ORR (defined in the RECIST 1.1 as complete response rate + partial response rate) measured by the appropriate radiological test in HER2-positive MBC patients with measurable disease (Phase II).

Sample Size:

Phase I: following the 3+3 rule, a minimum of 6 and a maximum of 12 patients will be recruited.

Phase II:Assuming 10% drop-out rate, 48 patients are required to enter the study.

The duration of the study, from first patient visit to last patient visit will be approximately 42 months.


Condition Intervention Phase
Breast Cancer
Drug: dasatinib plus trastuzumab plus 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 Trial of Dasatinib in Combination With Trastuzumab and Paclitaxel in the First Line Treatment of Her2-Positive Metastatic Breast Cancer (Mbc) Patients

Resource links provided by NLM:


Further study details as provided by Spanish Breast Cancer Research Group:

Primary Outcome Measures:
  • To determine the maximum tolerated dose (MTD) and recommended phase II dose (RPD) of dasatinib in combination with fixed doses of trastuzumab and paclitaxel in HER2-positive MBC patients (Phase I). [ Time Frame: 6-12 months 3,5 years since the beginning of the study ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To characterize the safety of the combination (in both phase I and phase II). [ Time Frame: 3,5 years 3,5 years since the beginning of the study ] [ Designated as safety issue: Yes ]
  • To evaluate the Clinical Benefit Rate (CBR) [ Time Frame: 3,5 years since the beginning of the study ] [ Designated as safety issue: No ]
  • Time to Progression (TTP) [ Time Frame: 3,5 years since the beginning of the study ] [ Designated as safety issue: No ]
  • Progression Free Survival (PFS) [ Time Frame: 3,5 years since the beginning of the study ] [ Designated as safety issue: No ]
  • Response Duration (RD) (in the phase II). [ Time Frame: 3,5 years since the beginning of the study ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: July 2011
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dasatinib plus trastuzumab plus paclitaxel
Eligible patients will be enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib will be administered orally in two dose levels 100 and 140 mg QD (a -1 dose level is included just in case dose de-escalation is needed). Treatment will be repeated on Day 1 of a 28-day cycle until radiographic or symptomatic progression or unacceptable toxicity occurs. Only in the phase I, the first cycle will last 38 days.
Drug: dasatinib plus trastuzumab plus paclitaxel
Eligible patients will be enrolled and treated with 4-week cycles of trastuzumab 2 mg/kg IV weekly (following a loading dose of 4 mg/kg in cycle 1) and paclitaxel 80 mg/m2 weekly x 3 weeks followed by a rest period of 7 days. Dasatinib will be administered orally in two dose levels 100 and 140 mg QD (a -1 dose level is included just in case dose de-escalation is needed). Treatment will be repeated on Day 1 of a 28-day cycle until radiographic or symptomatic progression or unacceptable toxicity occurs. Only in the phase I, the first cycle will last 38 days.

  Eligibility

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

Inclusion Criteria:

  • Female with histologically confirmed breast cancer with documented metastasis.

    • Patients must have HER-2 overexpression by immunohistochemistry (3+, Herceptest; DAKO) or a positive fluorescence in situ hybridization for HER2 amplification evaluated by central laboratory. It is recommended that a formalin-fixed paraffin embedded (FFPE) tumor tissue block from the metastatic site (or the primary tumor, if metastatic site not available) required for HER2 testing are provided.
    • Patients can have measurable or non measurable disease for the Phase I part. For the Phase II only patients with measurable disease defined per RECIST 1.1 will be included.
    • Signed Written Informed Consent.
    • Patients with Performance Status (ECOG) of 0 or 1.
    • Number of previous therapies allowed or previous therapies may have included:

      1. Chemotherapy: no prior chemotherapy for MBC is permitted. Patients treated with adjuvant chemotherapy regimens based on taxanes are allowed to be included if they are fully recovered of any taxane associated toxicity and a minimum of 12 months have elapsed from the end of this therapy.
      2. Hormonal Therapy: patients may have had prior hormonal therapy. All hormonal agents must be discontinued at least 3 weeks prior to study entry.
      3. Radiation Therapy: patients may have had prior radiation therapy that has not exceeded 25% of the bone marrow reserve. A minimum of 21 days must have elapsed between the last dose of radiation and registration into the study. Patients must have recovered from any acute toxic effects from radiation prior to registration. Lesions that have been irradiated cannot be included as sites of measurable disease for the phase II unless clear tumor progression, according to RECIST criteria, has been documented in these lesions since the end of radiation therapy.
      4. Previous Surgery: previous surgery is permitted provided that wound healing has occurred.
      5. Anti-HER2 Therapies: no prior anti-HER2 therapy for MBC is permitted. Patients treated with adjuvant anti-HER2 therapies (including but not limited to trastuzumab and lapatinib) are allowed to be included if a minimum of 12 months have elapsed from the end of this therapy.
    • Adequate Organ Function.
    • Ability to take oral medication (dasatinib must be swallowed whole).
    • Patient, age 18 years old.
    • Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy.

Exclusion Criteria:

  • Women who are pregnant or breastfeeding.
  • Patients with known brain metastases.
  • No malignancy [other than the one treated in this study] which required radiotherapy or systemic treatment within the past 5 years.
  • Concurrent medical condition which may increase the risk of toxicity, including: Pleural or pericardial effusion of any grade.
  • Cardiac Symptoms; any of the following should be considered for exclusion:

    1. Uncontrolled angina, congestive heart failure or MI within (6 months)
    2. Patients with intercurrent cardiac dysfunction or LVEF < 50%.
    3. Diagnosed congenital long QT syndrome.
    4. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
    5. Prolonged QTc interval on pre-entry electrocardiogram (450 msec).
    6. Patients with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration.
  • History of significant bleeding disorder unrelated to cancer, including:

    1. Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease).
    2. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).
    3. Ongoing or recent (3 months) significant gastrointestinal bleeding.
  • Patients with known allergy to any of the study drugs or their components.
  • Pre-existent toxicities of severity grade 2 due to previous anti-cancer treatments.
  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: NCT01306942

Contacts
Contact: Eva Carrasco, MD +34916592870 evacarrasco@geicam.org
Contact: Andres Hernando, BD +34916592870 ahernando@geicam.org

Locations
Spain
Instituto Catalán de Oncología de Barcelona Recruiting
Hospitalet de Llobregat, Barcelona, Spain, 08907
Principal Investigator: Ander Urruticoechea, MD.         
Complejo Hospitalario Universitario A Coruña Active, not recruiting
A Coruña, Spain, 15006
Hospital Clinic i Provincial Active, not recruiting
Barcelona, Spain, 08036
Hospital Universitario Virgen de la Victoria Active, not recruiting
Málaga, Spain, 29010
Instituto Valenciano de Oncología Active, not recruiting
Valencia, Spain, 46009
Sponsors and Collaborators
Spanish Breast Cancer Research Group
Bristol-Myers Squibb
Investigators
Principal Investigator: Alberto Ocaña, MD Complejo Hospitalario Universitario de Albacete
  More Information

Additional Information:
No publications provided

Responsible Party: Spanish Breast Cancer Research Group
ClinicalTrials.gov Identifier: NCT01306942     History of Changes
Other Study ID Numbers: GEICAM/2010-04
Study First Received: February 24, 2011
Last Updated: June 7, 2013
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Spanish Breast Cancer Research Group:
HER2+ metastatic breast cancer
first line treatment

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

ClinicalTrials.gov processed this record on October 29, 2014