Terminated due to low accrual and toxicity concerns.

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.

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.

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 II-IV; 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.

Only Phase 1 enrolled participants, however, the study was terminated early. The Phase 2 arm did not open to accrual.

18 months

Early study termination by mutual decision of the Sponsor and the Investigator due to lower than expected accrual and toxicities concerns. Only the Phase 1 arm opened to accrual; Phase 2 did not open to accrual.