An Open-Label, Phase Ib/II Clinical Trial Of Cdk 4/6 Inhibitor, Ribociclib (Lee011), In Combination With Trastuzumab Or T-Dm1 For Advanced/Metastatic Her2-Positive Breast Cancer.

Inclusion Criteria

• Participants must have histologically confirmed invasive breast cancer, with locally advanced or metastatic disease. Patients without pathologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
• The primary tumor, and/or metastasis must have been tested for ER, PR and HER 2, and be HER2 positive as defined by the 2013 ASCO-CAP guidelines.
• Measureable disease by RECIST 1.1 (at least one lesion that can be accurately measured in at least one dimension > 20mm with conventional imaging techniques or > 10mm with spiral CT or MRI) or evaluable disease. Bone lesions (blastic, lytic, or mixed) in the absence of measurable disease as defined above are also acceptable.
• Prior treatment
• Cohort A:
• Prior treatment with at least one regimen containing Trastuzumab and taxane.
• No prior treatment with T-DM1 that was discontinued due to disease progression or toxicity.
• No more than 4 prior lines of therapy in the metastatic setting.
• Cohort B:
• Must have received prior Trastuzumab, pertuzumab, and T-DM1 in neo-adjuvant, adjuvant, or metastatic setting.
• No limit on prior lines of therapies.
• Cohort C:
• Must have received prior Trastuzumab, pertuzumab, and T-DM1 in neo=adjuvant, adjuvant, or metastatic setting.
• Maximum of 5 prior lines of therapy for metastatic disease.
• Prior treatment with fulvestrant is permitted.
• Age ≥ 18 years.
• ECOG performance status 0-2 (see Appendix A)
• Participants must have adequate organ and bone marrow function as defined below:
• Absolute neutrophil count ≥1.5 x 109/L
• Platelets ≥100 x 109/L
• Hemoglobin ≥ 9 g/dL
• Total bilirubin 160 mmHg or 5 mIU/mL).
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for 8 weeks after study drug discontinuation. Highly effective contraception methods include:
• Total abstinence when this is in line with the preferred and usual lifestyle of the patient.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient
• Combination of the two following
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository.
• Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
• Sexually active males unless they use a condom during intercourse while taking the drug and for 4 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.