This is a single-centre study comprising two phases: a lead-in phase Ib and a phase II randomized portion.

Lead-in Phase Ib study A lead-in phase I study will be built into this protocol to confirm the dose of lenvatinib that can safely be combined with letrozole.

We expect that the optimal phase II dose level will be determined after recruiting 12-18 subjects into phase Ib. This dose level will be the one to be tested in the phase II portion of the study.

Phase II open label study In this part of the study, eligible patients will be treated with single agent lenvatinib at the phase II recommended dose for 2 weeks, followed by lenvatinib combined with letrozole 2.5mg daily for 12 weeks.

A total of 30 patients with ER positive breast cancer and measurable primary tumor will be enrolled over a period of 24-30 months

Hypothesis:

We hypothesize that combining a RET inhibitor such as lenvatinib with endocrine therapy may potentiate anti-tumor effects in ER+ breast cancers in the clinic. Given that RET inhibition is the primary mechanism of action of lenvatinib, we further hypothesize that RET expression in the breast tumor may be a biomarker that predicts for better response to the combination of a RET inhibitor and endocrine therapy in both a neoadjuvant (Part A) and a metastatic (Part B) setting.

Primary Objectives

1. To confirm the dose of lenvatinib that can be safely combined with letrozole in the lead-in Phase Ib part of the study.
2. Part A (For patients with non-metastatic breast cancer undergoing neoadjuvant treatment) : To determine the overall clinical response (measured by ultrasound) and pathological complete response rate after 2 weeks of neoadjuvant single agent lenvatinib followed by 12 weeks of letrozole combined with lenvatinib and compare with historical controls treated with single agent letrozole.
3. Part B (For patients with metastatic breast cancer and who have tumor lesion that can be serially biopsied safely): to determine the clinical response (measured by RECIST criteria) after 2 weeks of single agent lenvatinib followed by continuous dual therapy of lenvatinib and letrozole, until time of progression or intolerability.

Secondary Objectives

1. To evaluate the overall biological effects (Ki67 changes, histological response, apoptosis, RET and downstream targets such as AKT and ERK) of 2 weeks of single agent lenvatinib, and of letrozole + lenvatinib, in ER positive breast cancer, respectively.

2. To identify biological predictors for treatment response to letrozole + lenvatinib in ER positive breast cancer using pharmacokinetics, pharmacogenetics, genomics and proteomics strategies.

3. To compare the following parameters between RET positive versus RET negative, ER positive breast cancer:

   • Part A :

i. Clinical response (measured by ultrasound) and biological effects of 2 weeks of single agent lenvatinib, ii. Clinical response (measured by ultrasound) and biological effects after 2 weeks of single agent lenvatinib followed by 12 weeks of letrozole combined with lenvatinib

-Part B : i. Clinical response measured by RECIST criteria after 2 weeks of single agent lenvatinib followed by letrozole combined with lenvatinib ii. Progression-free and overall survival with letrozole combined with lenvatinib

Inclusion Criteria:

• Female, age ≥ 18 years.

• Histologic or cytologic diagnosis of breast carcinoma.

• Part A: T1-4 breast cancer with measurable primary breast tumor, defined as palpable tumor with both diameters 2.0cm or greater as measured by caliper. Newly diagnosed metastatic patients with measurable primary breast tumor ≥2cm are eligible provided that there are plans for toilet mastectomy after completing 14 weeks of pre-operative drug therapy. Patients must not have received prior chemotherapy or hormonal therapy for the treatment of the current breast cancer.

• Part B: Patients with metastatic breast cancer with measurable tumor by RECIST criteria.Patients previously treated with letrozole are eligible if they progressed on letrozole ≥1 year after adjuvant treatment, or ≥ 6 months in the metastatic setting.

• ECOG 0-1.

• Estimated life expectancy of at least 12 weeks.

• Adequate organ function including the following:

  • Bone marrow:
  • Absolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 109/L
  • Platelets ≥ 100 x 109/L
  • Hepatic:
  • Bilirubin ≤ 1.5 x upper limit of normal (ULN),
  • ALT or AST ≤ 2.5x ULN, (or ≤5 X with liver metastases)
  • Renal:

Creatinine ≤ 1.5x ULN

• Post-menopausal women. Post-menopausal status is defined either by

• Age ≥ 60 years and one year or more of amenorrhea
• Age < 60 years and one year or more of amenorrhea (in the absence of ovarian suppression) and with estradiol and FSH levels consistent with menopause, *Treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression for Part A (patients with non-metastatic disease receiving the study treatment as neoadjuvant therapy).

However, in Part B (patients with metastatic disease), pre-menopausal women who are treated with medical ovarian suppression with post-menopausal levels of estradiol (institutional limits) at time of study entry and who will continue to be suppressed with 4-weekly LHRH agonist during study treatment may be enrolled. If these patients were previously on 12-weekly long-acting LHRH agonist, this has to be switched to 4-weekly LHRH agonist while the patient is on study treatment.

• Signed informed consent from patient or legal representative.

Exclusion Criteria:

• Treatment within the last 30 days with any investigational drug.
• Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy.
• Major surgery within 28 days of study drug administration.
• Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
• Pregnancy.
• Breast feeding.
• Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
• Active bleeding disorder or bleeding site.
• Non-healing wound.
• Poorly controlled diabetes mellitus.
• Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
• Symptomatic brain metastasis.
• History of significant neurological or mental disorder, including seizures or dementia.