Ensayos clínicos

Inclusion Criteria:

• Have a diagnosis of HR+, HER2+ advanced breast cancer:
  • To fulfill the requirement of HR+ disease, the primary tumor or metastatic lesion of the breast cancer must express at least one of the hormone receptors (estrogen receptor [ER] or progesterone receptor [PgR]) by immunohistochemistry (IHC). Estrogen receptor and PgR assays are considered positive if there are at least 1% positive tumor nuclei in the sample as defined in the relevant American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guidelines (Hammond et al. 2010);
  • To fulfill the requirement of HER2+ disease, the primary tumor or metastatic lesion of the breast cancer must demonstrate overexpression of HER2 by either IHC (3+) or gene amplification by positive in-situ hybridization (ISH) as defined in the relevant ASCO/CAP HER2 guidelines (Wolff et al. 2013);
  • Although not required as a protocol procedure, a patient with a new metastatic lesion should be considered for fresh biopsy (whenever possible) to reassess HR and HER2 status prior to study entry if clinically indicated. The most recent receptor testing should be used to determine eligibility.
• Have unresectable locally advanced recurrent breast cancer or metastatic breast cancer (all termed advanced disease).
• Have adequate tumor tissue (newly obtained biopsy; otherwise archived tissue) available prior to randomization.
  • Note: Sites should confirm the availability of adequate tumor tissue with the pathological laboratory prior to randomization.
• Have measurable and/or non-measurable disease according to RECIST version 1.1 (Eisenhauer et al. 2009)
• Have previously received:
  • at least 2 HER2-directed therapies for advanced disease;
  • prior HER2-directed therapies could be in combination with chemotherapy or endocrine therapy or as single agent;
  • exposure to dual HER2 blockade (for example, combination trastuzumab and pertuzumab) is considered as 1 prior HER2-directed therapy;
  • patient must have received T-DM1 in any disease setting;
  • prior trastuzumab and/or pertuzumab and/or lapatinib are allowed in any disease setting.
• Patient must have received a taxane in any disease setting.
• Patients may have received any endocrine therapy (excluding fulvestrant).
• Have postmenopausal status due to either surgical/natural menopause or chemical ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin or radiation-induced ovarian suppression postmenopausal status due to surgical/natural menopause is defined as meeting one of the following conditions:
  • prior bilateral oophorectomy;
  • age ≥ 60 years;
  • age < 60 years and amenorrheic (in the absence of tamoxifen, toremifene, ovarian suppression, or chemotherapy) for at least 12 months. Follicle-stimulating hormone (FSH) and estradiol must be in the postmenopausal range.
• Postmenopausal status due to radiation-induced ovarian suppression must be confirmed by FSH and estradiol level in the postmenopausal range.
• Have a performance status (PS) of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) scale.
• Must have left ventricular ejection fraction (LVEF) of 50% or higher at baseline (determined by echocardiography or multiple-gated acquisition scanning).
• Have adequate organ function, including:
  • hematologic: absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L, and hemoglobin ≥ 8 g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion;
  • hepatic: total bilirubin ≤ 1.5 × the upper limit of normal (ULN) (except in cases of known Gilbert’s syndrome where ≤ 2.0x ULN is allowed) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN. If liver metastases are present, AST and ALT ≤ 5 × ULN are acceptable;
  • renal: serum creatinine ≤ 1.5 × ULN.
• Have a negative serum pregnancy test at baseline (within 14 days prior to randomization) and agree to use medically approved precautions to prevent pregnancy during the study and for 12 weeks following the last dose of abemaciclib if postmenopausal status is due to ovarian suppression with a GnRH agonist or induced by radiation.
• Have discontinued previous localized radiotherapy for palliative purposes or for lytic lesions at risk of fracture at least 2 weeks prior to randomization and recovered from the acute effects of therapy (until the toxicity resolves to either baseline or at least Grade 1) except for residual alopecia or peripheral neuropathy.
• Have discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and endocrine therapy), except trastuzumab, for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug, and recovered from the acute effects of therapy (until the toxicity resolves to either baseline or at lease Grade 1) except for residual alopecia and peripheral neuropathy.
• Are female and ≥ 18 years of age.
• Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.
• Have given written informed consent prior to any study-specific procedures.
• Are able to swallow capsules.

Exclusion Criteria:

• Have visceral crisis. Visceral crisis is not the mere presence of visceral metastases but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of the disease.
• Have known central nervous system (CNS) metastases that are untreated, symptomatic, or require steroids to control symptoms.
  • Note: patients with a history of treated brain- metastases are eligible.
• Treated brain-metastases are defined as those having no evidence of progression for ≥ 2 months and no ongoing requirement for corticosteroids, as ascertained by clinical examination and by brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) during the screening period
• Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥ 2 weeks before randomization.
• Treatment for brain metastases may include whole brain radiation (WBRT), radiosurgery, or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection must be at least 8 weeks from surgery. A wash out period of at least 8 weeks is required after end of WBRT.
• Have had major surgery within 14 days prior to randomization to allow for post-operative healing of the surgical wound and site(s).
  • Note: A surgery is qualified as major per investigator/surgeon judgment based on the required recovery period, both from general patient status and post-operative healing perspectives.
• Have received prior treatment with any CDK 4 and CDK 6 inhibitor (or participated in any CDK 4 and CDK 6 inhibitor clinical trial for which treatment assignment is still blinded).
• Have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of randomization for a nonmyelosuppressive or myelosuppressive agent, respectively.
• Have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis).
• Have a history within the last 6 months of symptomatic congestive heart failure, myocardial infarction, or unstable angina.
• Have a personal history within the last 12 months of any of the following conditions: syncope of cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest.
• Have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission with no therapy for a minimum of 3 years. For patients with history of other cancers within 3 years and considered of very low risk of recurrence per investigator’s judgment (for example, papillary thyroid cancer treated with surgery), eligibility is to be discussed with Lilly clinical research physician (CRP).
• Have active bacterial infection (that is to say, requiring IV antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (for example, known human immunodeficiency virus [HIV] positivity or known active or inactive hepatitis carrier [for example, hepatitis B surface antigen (HBsAg) positive]). Screening is not required for enrollment.
• Have received any recent (within 28 days prior to randomization) live virus vaccination.
• Are currently enrolled in a clinical trial involving investigational product (IP) or non-approved use of a drug or device (other than the IP/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
• Hypersensitivity to trastuzumab, murine proteins, fulvestrant, or to any of the excipients.