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Dasatinib In Combination With Trastuzumab And Paclitaxel In First Line Treatment Of Her2-Positive MBC Patients

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ClinicalTrials.gov Identifier: NCT01306942
Recruitment Status : Active, not recruiting
First Posted : March 2, 2011
Last Update Posted : January 17, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Spanish Breast Cancer Research Group

Brief Summary:
This is a single-arm, open-label, phase I/II study. In the phase I, patients with Human Epidermal Growth Factor Receptor 2 (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 patients will be treated at that dose to evaluate the efficacy and safety of the combination in the phase II.

Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Drug: Dasatinib Drug: Trastuzumab Drug: Paclitaxel Phase 1 Phase 2

Detailed Description:

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 once daily (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 in all patients (both in the phase I as in the phase II) until radiographic or symptomatic progression or unacceptable toxicity occurs. Only in the phase I and in all patients included in every different dose level, the first cycle will last 38 days.

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).

Secondary Objective(s):

  • To characterize the safety of the combination (in both phase I and phase II).
  • To evaluate the Clinical Benefit Rate (CBR), Time to Progression (TTP), Progression Free Survival (PFS) and Response Duration (RD) (in the phase II).
  • To evaluate the pharmacokinetics (PK) of the combination (in the phase I and selected patients in the phase II if necessary).
  • To evaluate molecular characteristics that may be predictive of the activity (or lack of) and any correlation between the biological activity of the study treatment and the disease outcome.

Exploratory objective:

• To explore the correlation between the lymphocytosis and efficacy.

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Intervention Model: Single Group Assignment
Masking: None (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
Actual Study Start Date : July 2011
Actual Primary Completion Date : December 2013
Estimated Study Completion Date : June 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Dasatinib + trastuzumab + 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 once daily (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
Other Name: Sprycel
Drug: Trastuzumab
Other Name: Herceptin
Drug: Paclitaxel
Other Name: Taxol



Primary Outcome Measures :
  1. Incidence rate of dose limiting toxicity (DLT) within the first cycle of dasatinib in combination with trastuzumab and paclitaxel [ Time Frame: At the end of cycle 1 (38 days) in phase I ]
    DLT is defined as the occurrence of any of the following adverse events or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03), assessed as possibly, probably or definitively related to study drugs, occurring within the first cycle of study treatment: Need of any dose modification within the first cycle due to toxicity, grade 3 or 4 neutropenia complicated with fever ≥38.5° C or infection, grade 4 neutropenia (absolute neutrophil count (ANC)<0.5x1000000000/L) of at least 7 days duration, grade 3 thrombocytopenia complicated by hemorrhage, grade 4 thrombocytopenia, any grade 4 non-hematologic toxicity, grade 3 non-hematologic toxicities except nausea, vomiting, or diarrhea that can be controlled by appropriate medical intervention or prophylaxis, inability to resume dosing for cycle 2 at the current dose level within 14 days due to treatment related toxicity.

  2. Maximum Tolerated Dose (MTD) of dasatinib in combination with trastuzumab and paclitaxel [ Time Frame: At the end of cycle 1 (38 days) in phase I ]
    MTD is determined by testing increasing doses of dasatinib on dose escalation cohorts 3 to 6 patients per dose level. MTD reflects the highest dose tested in which a DLT is experienced by 0 out of 3 or 1 out of 6 patients among the dose levels

  3. Recommended Phase II Dose (RP2D) of dasatinib in combination with trastuzumab and paclitaxel (Phase I). [ Time Frame: At the end of cycle 1 (38 days) in phase I ]
    The RP2D is decided by the investigators taken into consideration the information obtained in the study and based on the MTD. To define the RP2D, information about toxicity observed during the full treatment will be taken into consideration (relative dose intensity and toxicity observed).

  4. Objective Response Rate (ORR) [ Time Frame: From treatment start until the date of first documented progression or date of death, whichever came first, assessed up to 100 months ]
    Tumor response to be assessed using RECIST 1.1 criteria. ORR is defined as the percentage of patients with a complete or partial response out of the patients who had measurable disease at baseline.


Secondary Outcome Measures :
  1. The Number of Participants Who Experienced Adverse Events (AE) [ Time Frame: Through study treatment up to 1 month after discontinuation in phase I and II ]
    Safety will be assessed by standard clinical (blood pressure, pulse and body temperature, electrocardiogram (ECG), left ventricular ejection fraction (LVEF)) and laboratory tests (hematology: hemoglobin, platelet count, red blood cells (RBC), white blood cells (WBC) with differential (neutrophils) and absolute lymphocyte count, and serum chemistry: alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, creatinine, sodium, potassium, magnesium, phosphate and calcium). Adverse events grade will be defined by the NCI CTCAE v 4.03.

  2. To evaluate the Clinical Benefit Rate (CBR) [ Time Frame: From treatment start until the date of first documented progression or date of death, whichever came first, assessed up to 100 months ]
    CBR is defined as the percentage of patients with a complete or partial response plus stable disease lasting at least 6 months out of the efficacy population.

  3. Time to Progression (TTP) [ Time Frame: From treatment start until the date of first documented progression or date of death, whichever came first, assessed up to 100 months ]
    TTP is defined as the time from the date of the first dose to the first date of objectively determined progressive disease. For patients not known to have objectively-determined progressive disease, TTP will be censored at the date of the last objective progression-free assessment. For patients who receive subsequent systemic anticancer therapy (after discontinuation from the study treatment) prior to objective disease progression, TTP will be censored at the date of last objective progression-free assessment prior to the initiation of post-discontinuation systemic anticancer therapy.

  4. Progression Free Survival (PFS) [ Time Frame: From treatment start until the date of first documented progression or date of death, whichever came first, assessed up to 100 months ]
    PFS is defined as the time from the date of the first dose to the first date of objectively determined progressive disease or death from any cause. For patients not known to have died as of the data cut-off date and who do not have objectively-determined progressive disease, PFS will be censored at the date of the last objective progression-free assessment. For patients who receive subsequent systemic anticancer therapy (after discontinuation from the study treatment) prior to objective disease progression or death, PFS will be censored at the date of last objective progression-free assessment prior to the initiation of post-discontinuation systemic anticancer therapy.

  5. Response Duration (RD) [ Time Frame: From treatment start until the date of first documented progression or date of death, whichever came first, assessed up to 100 months ]
    RD is defined as the time from the date when the measurement criteria are met for complete response (CR) or partial response (PR) (whichever status is recorded first) until the date of first observation of disease progression or death occurred. For responding patients not known to have died as of the data cut-off date and who do not have progression, duration of response will be censored at the date of last visit with adequate assessment. For responding patients who receive subsequent anticancer therapy (after discontinuation from the study treatment) prior to progression, duration of response will be censored at the date of last visit with adequate assessment prior to the initiation of post-discontinuation anticancer therapy.

  6. Dasatinib plasma concentration (pharmacokinetics (PK)) [ Time Frame: From cycle 1 to cycle 3 day 1 ]
    The PK will determine whether dasatinib influences the pharmacology of paclitaxel and trastuzumab. Blood samples will be taken at the times defined in the protocol

  7. Immunohistochemical expression analysis of proteins after treatment [ Time Frame: From cycle 1 to cycle 3 day 1 ]
    Phosphorylated SRC (p-SRC), non phosphorylated SRC (c-SRC), phosphorylated AKT (p-AKT) and phosphorylated extracellular signal-regulated kinases (p-ERK) 1 and 2 expression will be analyzed in the tumor tissue (if available), blood samples and skin biopsies taken at the times defined in the protocol, only in patients accepting to participate. All biological data will be correlated with the activity of study treatment and disease outcome.

  8. Correlation between lymphocytosis and efficacy. [ Time Frame: At the end of cycle 1 (38 days) ]
    Response rate according to RECIST 1.1 criteria will be correlated with early appearance of lymphocytosis.



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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Female with histologically confirmed breast cancer with documented metastasis.
  2. Patients must have Human Epidermal Growth Factor Receptor 2 (HER2) 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.
  3. 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.
  4. Signed Written Informed Consent.
  5. Target Population:

    1. Patients with Performance Status (ECOG) of 0 or 1.
    2. Number of previous therapies allowed or previous therapies may have included:

      • 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.
      • Hormonal Therapy: patients may have had prior hormonal therapy. All hormonal agents must be discontinued at least 3 weeks prior to study entry.
      • 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.
      • Previous Surgery: previous surgery is permitted provided that wound healing has occurred.
      • 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.
    3. Adequate Organ Function (...).
    4. Ability to take oral medication (dasatinib must be swallowed whole).
    5. Concomitant Medications

    i) Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy (discontinue St. Johns Wort at least 5 days before starting dasatinib) ii) Biphosphonates must not be initiated within 28 days prior to study therapy

  6. Age and sex:

    f) Patient, age 18 years old. g) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 4 weeks after the last dose of study drug to minimize the risk of pregnancy. (...)

Exclusion Criteria:

  1. Sex and reproductive status:

    1. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug
    2. Women who are pregnant or breastfeeding.
    3. Women with a positive pregnancy test
  2. Target Disease Exceptions:

    a) Central nervous system (CNS) metastases which are not well controlled. Eligible patients must be asymptomatic, cannot be receiving steroids or anticancer treatment, and must be enrolled at least 1 month after the end of the radiotherapy treatment

  3. Medical History and Concurrent Diseases

    1. No malignancy [other than the one treated in this study] which required radiotherapy or systemic treatment within the past 5 years.
    2. Concurrent medical condition which may increase the risk of toxicity, including: Pleural or pericardial effusion of any grade.
    3. Cardiac Symptoms; any of the following should be considered for exclusion:

    i) Uncontrolled angina, congestive heart failure or myocardial infarction (MI) within (6 months) ii). Patients with intercurrent cardiac dysfunction or left ventricular ejection fraction (LVEF) < 50%.

    iii) Diagnosed congenital long QT syndrome. iv) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).

    v) Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (450 msec).

    vi) Patients with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib administration.

    d) History of significant bleeding disorder unrelated to cancer, including: i) Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease). ii) Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).

    iii) Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding.

  4. Allergies and Adverse Drug Reactions

    a) Patients with known allergy to any of the study drugs or their components.

  5. Prohibited Treatments and/or Therapies

    a) 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) i) quinidine, procainamide, disopyramide ii) amiodarone, sotalol, ibutilide, dofetilide iii) erythromycin, clarithromycin iv) chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide v) cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.

    b) Concurrent anti-cancer therapy c) Potent CYP3A4 inhibitors

  6. Other exclusion criteria:

    1. Patients who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
    2. Patients with active or uncontrolled infections or with serious illnesses or medical conditions that would not permit the patient to be managed according to the protocol.
    3. Patients unable or unwilling to give written informed consent prior to study participation.
    4. Pre-existent motor or sensory neurotoxicity of severity ≥ grade 2 according to NCI common toxicity criteria (version 4.03).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01306942


Locations
Spain
Instituto Catalán de Oncología de Barcelona (Hospital Duran i Reynalds)
Hospitalet de Llobregat, Barcelona, Spain, 08907
Hospital Alvaro Cunqueiro
Vigo, Pontevedra, Spain, 36204
Complejo Hospitalario Universitario A Coruña
A Coruña, Spain, 15006
Hospital Clinic i Provincial
Barcelona, Spain, 08036
Hospital General Universitario Gregorio Marañón
Madrid, Spain, 28007
Hospital Clínico Universitario Virgen de la Victoria
Málaga, Spain, 29010
Hospital Universitario Virgen del Rocío
Sevilla, Spain, 41013
Instituto Valenciano de Oncología
Valencia, Spain, 46009
Sponsors and Collaborators
Spanish Breast Cancer Research Group
Bristol-Myers Squibb
Investigators
Study Director: Study Director Complejo Hospitalario Universitario de Albacete

Additional Information:
Responsible Party: Spanish Breast Cancer Research Group
ClinicalTrials.gov Identifier: NCT01306942     History of Changes
Other Study ID Numbers: GEICAM/2010-04
2010-023304-27 ( EudraCT Number )
First Posted: March 2, 2011    Key Record Dates
Last Update Posted: January 17, 2018
Last Verified: January 2018

Keywords provided by Spanish Breast Cancer Research Group:
HER2 positive breast cancer
first line treatment
Dasatinib
SRC kinase
Trastuzumab resistance

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