Clinical Trials /

Vinorelbine With Trastuzumab Emtansine in Pre-Treated HER2-Positive Metastatic Breast Cancer

NCT02658084

Description:

The study proposes to evaluate the safety and efficacy of the combination of trastuzumab emtansine (T-DM1) and vinorelbine in HER2+ metastatic breast cancer patients.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Vinorelbine</span> With <span class="go-doc-concept go-doc-intervention">Trastuzumab Emtansine</span> in Pre-Treated <span class="go-doc-concept go-doc-biomarker">HER2</span>-Positive <span class="go-doc-concept go-doc-disease">Metastatic Breast Cancer</span>

Title

  • Brief Title: Vinorelbine With Trastuzumab Emtansine in Pre-Treated HER2-Positive Metastatic Breast Cancer
  • Official Title: A Phase I/II Study to Evaluate the Safety and Efficacy of Vinorelbine With Trastuzumab Emtansine in Pre-Treated HER2-Positive Metastatic Breast Cancer
  • Clinical Trial IDs

    NCT ID: NCT02658084

    ORG ID: 20151055

    Trial Conditions

    Breast Cancer

    Metastatic Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    Vinorelbine Vinorelbine tartrate, Navelbine Phase 1: T-DM1 + Vinorelbine, Phase 2: T-DM1 + RP2D Vinorelbine
    Trastuzumab Emtansine Kadcyla, T-DM1, Trastuzumab-MCC-DM1 Phase 1: T-DM1 + Vinorelbine, Phase 2: T-DM1 + RP2D Vinorelbine

    Trial Purpose

    The study proposes to evaluate the safety and efficacy of the combination of trastuzumab
    emtansine (T-DM1) and vinorelbine in HER2+ metastatic breast cancer patients.

    Detailed Description

    This is a Phase I/II, single arm, open-label clinical trial designed to establish the
    recommended phase II dose (RP2D) of vinorelbine with a fixed dose of trastuzumab emtansine.
    The study will also evaluate the safety and efficacy of the RP2D in patients with human
    epidermal growth factor receptor 2 (HER2)-positive metastatic, locally advanced, or
    unresectable breast cancer. The study will be opened to accrual at the University of Miami
    Sylvester Comprehensive Cancer Center (SCCC) main campus and constituent satellite sites,
    Deerfield Beach and Plantation.

    This phase I/II study will have a total of 50 enrolled patients, taking into account 10%
    drop-out in the phase II follow-up. The duration anticipated to enroll all study subjects in
    Phase I/II is 2 years. The estimated duration for the Investigators to complete this study
    (Phase I/II) is 4.5 to 5 years.

    For the phase I portion, standard 3+3 dose escalation/de-escalation design will be applied.
    Approximately 15 to 21 patients will be needed to establish the recommended phase II dose
    (RP2D). For the phase II portion of the study, up to 35 patients will be treated at the RP2D
    (MTD) including 6 patients treated at RP2D in phase I. Patients may remain on treatment with
    the combination until disease progression or unmanageable toxicity.

    Tumor assessments will be conducted every 6 weeks (7 days) to week 18. Thereafter, these
    assessments will be done every 12 weeks (7 days). These will shall occur regardless of dose
    delays or dose interruptions, until Investigator-assessed progressive disease (PD), or
    death, whichever occurs first. More frequent tumor assessments may be performed as
    clinically indicated, at the discretion of the treating Investigator.

    For the phase II portion of the study - patients who discontinue treatment for reasons other
    than PD will continue to have required tumor assessments completed until PD or the
    initiation of a new therapy. Once patients have progressed, they will be followed for
    survival approximately every 3 months for at least 3 years. Subsequent anti-cancer therapies
    will be documented until study completion.

    Patients who are discontinued from study treatment will return for the Study Treatment
    Discontinuation Visit approximately 30 days (7 days) after the last dose of study
    treatment.

    Trial Arms

    Name Type Description Interventions
    Phase 1: T-DM1 + Vinorelbine Experimental One cycle of Trastuzumab Emtansine (T-DM1)/Vinorelbine combination treatment is defined as 21-days (i.e. 3 weeks). The recommended (starting) dose of trastuzumab emtansine is 3.6 mg/kg given as an intravenous infusion on Day 1 of every 21-day cycle. The starting dose of Vinorelbine is 22.5 mg/m2 given as a direct intravenous push over 6-10 minutes on day 1 and day 8 of every 3-week (i.e. 21-day) cycle. Participants will be treated until documented disease progression or other criteria for discontinuation. Approximately 15 to 21 patients will be needed to establish the recommended phase II dose (RP2D). Vinorelbine, Trastuzumab Emtansine
    Phase 2: T-DM1 + RP2D Vinorelbine Experimental One cycle of trastuzumab emtansine (T-DM1)/vinorelbine combination treatment is defined as 21-days (i.e. 3 weeks). Participants will receive the recommended Phase 2 Dose (RPSD) of Vinorelbine with the fixed dose (3.6 mg/kg) of Trastuzumab Emtansine. Participants will be treated until documented disease progression or other criteria for discontinuation. Up to 35 patients will be treated at the RP2D (MTD) including 6 patients treated at RP2D in phase I. Vinorelbine, Trastuzumab Emtansine

    Eligibility Criteria

    Inclusion Criteria:

    1. Histologically or cytologically documented breast cancer.

    2. Metastatic or unresectable locally advanced/recurrent breast cancer.

    3. HER2-positive disease documented as: Immunohistochemistry (IHC) 3+ positive, and/or
    Fluorescence in situ hybridization (FISH) 2.0, and/or gene copy number greater than
    6, on previously collected tumor or metastatic site. IHC testing, FISH assay(s), and
    gene copy number may all have been performed; however, a positive result from only
    one of the above is required for eligibility.

    4. Documented disease progression on the last regimen by radiographic measurement
    (progression demonstrated by tumor markers only is unacceptable).

    5. Documented disease progression (by investigator assessment) after at least one
    regimen of HER2-directed therapy in the metastatic or unresectable locally
    advanced/recurrent setting.

    6. For patients with hormone receptor-positive disease: disease progression or
    recurrence in any setting on prior hormonal therapy, given with or without HER2
    directed therapy.

    7. Measurable or bone only disease.

    8. Prior treatment with a taxane, in the neoadjuvant, adjuvant, locally advanced or
    metastatic setting.

    9. A minimum of 6 weeks of prior trastuzumab for the treatment of metastatic or
    unresectable locally advanced/recurrent disease is required.

    10. Prior use of Pertuzumab in any setting is permitted (but not required).

    11. Prior use of Lapatinib in any setting is permitted (but not required).

    12. Age 18 years

    13. Life expectancy 3 months

    14. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. See Appendix
    C for details.

    15. Patients must have normal organ and marrow function as defined below:

    - absolute neutrophil count (ANC) >1,500 cells/mm3

    - platelets >100,000 cells/mm3

    - hemoglobin > 9.0 g/dL (Patients are permitted to receive transfused red blood
    cells to achieve this level.)

    - total bilirubin 1.5 X institutional upper limit of normal (ULN) [Note: For
    patients with previously documented Gilbert's syndrome, total bilirubin 3
    mg/dL.]

    - Aspartate aminotransferase (AST/SGOT) 2.5 X ULN

    - Alanine aminotransferase (ALT/SGPT) 2.5 X ULN

    - alkaline phosphatase (alk phos) 2.5 X ULN

    - serum creatinine < 1.5 X ULN

    16. International normalized ratio (INR) < 1.5 X ULN

    17. Left ventricular ejection fraction (LVEF) 50% by either echocardiogram (ECHO) or
    multiple-gated acquisition scan (MUGA).

    18. Negative results of serum pregnancy test for premenopausal women of reproductive
    capacity and for women < 12 months after menopause. For men and women of childbearing
    potential, agreement by the patient and/or partner to use two effective non-hormonal
    forms of barrier contraception at the same time, throughout treatment on study. Women
    should agree to continued use for at least 90 days after the end of treatment. Men
    should agree to continued use for at least 7 months after the end of treatment.
    Examples of non-hormonal barrier contraception include: condom or occlusive cap
    (diaphragm or cervical/vault caps) with spermicide.

    19. Ability to understand and willingness to sign a written informed consent and HIPAA
    document.

    Exclusion Criteria:

    1. Chemotherapy 21 days prior to first dose of study treatment

    2. If last dose of trastuzumab was:

    - 6mg/kg then 21 days prior to first dose of study treatment

    - 4mg/kg then 14 days prior to first dose of study treatment

    - 2mg/kg then 7 days prior to first dose of study treatment

    3. Lapatinib 14 days prior to first dose of study treatment

    4. Pertuzumab 21 days prior to first dose of study treatment

    5. Hormone therapy 7 days prior to first dose of study treatment

    6. Investigational therapy or any other such experimental therapy 28 days prior to
    first dose of study treatment

    7. Prior treatment with trastuzumab emtansine, (on or off a study protocol)

    8. Prior use of vinorelbine (in any setting).

    9. Previous radiotherapy for the treatment of unresectable, locally advanced, recurrent
    or metastatic breast cancer is not allowed if:

    - The last fraction of radiotherapy has been administered within 14 days prior to
    study enrollment

    - More than 25% of marrow-bearing bone has been irradiated

    10. Brain metastases that are untreated or symptomatic, or require any radiation,
    surgery, or continued steroid therapy to control symptoms from brain metastases
    within 14 days of study enrollment.

    11. History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity
    to trastuzumab or murine proteins.

    12. History of exposure to the following cumulative doses of anthracyclines:

    - Doxorubicin 550mg/m2

    - Liposomal doxorubicin >500 mg/m2

    - Epirubicin >900 mg/m2

    - Mitoxantrone > 120 mg/m2

    - If another anthracycline, or more than one anthracycline, has been used, the
    cumulative dose must not exceed the equivalent of 550 mg/m2 doxorubicin.

    13. Current peripheral neuropathy of Grade 3 per the NCI CTCAE, v4.0

    14. The patient has not recovered from any other acute toxicity (to Grade 1 as per NCI
    CTCAE v4.03) prior to study enrollment.

    15. History of other malignancy within the last 3 years, except for appropriately treated
    carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer,
    or other cancers with a similar outcome.

    16. Cardiopulmonary Function Criteria:

    - Current unstable ventricular arrhythmia requiring treatment

    - History of symptomatic congestive heart failure (CHF) as per New York Heart
    Association (NYHA) Classes IIIV; see Appendix D for details.

    - History of myocardial infarction or unstable angina within 6 months of study
    enrollment

    - History of a decrease in LVEF to < 40% or symptomatic CHF with previous
    trastuzumab treatment

    - Severe dyspnea at rest due to complications of advanced malignancy or requiring
    current continuous oxygen therapy

    17. Current severe, uncontrolled systemic disease (e.g., clinically significant
    cardiovascular, pulmonary, or metabolic disease)

    - Major surgical procedure or significant traumatic injury within 28 days -before
    enrollment or anticipation of the need for major surgery during the course of
    study treatment

    - Current pregnancy or lactation

    - Current known uncontrolled active infection with HIV, hepatitis B, and/or
    hepatitis C virus

    18. Any uncontrolled, intercurrent illness including but not limited to ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
    arrhythmia.

    19. Any other serious medical or psychiatric illness/condition likely in the judgment of
    the Investigator(s) to interfere or limit compliance with study
    requirements/treatment.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Phase 1 - Maximum Tolerated Dose (MTD) of Vinorelbine in combination with a fixed dose of Trastuzumab Emtansine.

    Phase 2 - Rate of Progression-Free Survival (PFS)

    Phase 1 - Rate of Participants Experiencing Adverse Events

    Secondary Outcome Measures

    Phase 2 - Clinical Benefit Rate (CBR)

    Phase 2 - Overall Survival (OS) Rate

    Phase 2 - Objective Response Rate (ORR)

    Trial Keywords

    HER2-Positive

    Metastatic Breast Cancer