Clinical Trials /

Neoadjuvant Lenvatinib Combined With Letrozole in Hormone Receptor Positive Breast Cancer



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

Related Conditions:
  • Breast Carcinoma
Recruiting Status:



Phase 1/Phase 2

Trial Eligibility



  • Brief Title: Neoadjuvant Lenvatinib Combined With Letrozole in Hormone Receptor Positive Breast Cancer
  • Official Title: Phase Ib Followed by Phase II Study of Pre-operative Treatment With Lenvatinib Combined With Letrozole in Post-menopausal Women With Newly Diagnosed Hormone Receptor Positive Breast Cancer With Measurable Primary Breast Tumor

Clinical Trial IDs

  • ORG STUDY ID: BR01/04/15
  • SECONDARY ID: 2015/00411
  • NCT ID: NCT02562118


  • Breast Cancer


Lenvatinib + LetrozoleLenvatinib + Letrozole


Background: Endocrine therapy is the standard treatment for hormone receptor positive breast cancer. However, both primary and acquired resistance occurs, and better strategies to improve treatment outcome and overcome resistance are urgently needed. There is known cross talk between RET and ER, and preclinical studies have suggested that combining a RET inhibitor with endocrine therapy may improve cell kill in breast cancer cell lines. Aim: To determine the safe dose of lenvatinib that can be co-administered with letrozole in a phase Ib study, followed by a phase II study to determine the efficacy of lenvatinib + letrozole in post-menopausal patients newly diagnosed with hormone receptor positive breast cancer in the neoadjuvant setting. Methods: Eligible patients will be treated with 2 weeks of single agent lenvatinib, followed by 12 weeks of lenvatinib + letrozole. Blood and tumor samples will be obtained from the patient serially to study tumor and host factors that may influence drug efficacy and toxicity. Importance of the proposed research: The combination of lenvatinib + letrozole may improve the treatment response in some ER+ breast cancers. The study will seek to identify biomarkers (eg tumor RET expression) that may select patients most likely to benefit from the combination therapy. Potential benefits and risks: The combination may improve treatment response. Adding lenvatinib may increase treatment risks, but these will be monitored closely. Pharmacokinetic analyses will also be performed to determine the drug levels achieved in the patients, and correlate that with treatment toxicity and efficacy.

Detailed Description

      Breast cancer is the commonest cancer among females in Singapore and worldwide. Approximately
      60-70% of breast cancers are hormone receptor positive and thus potentially sensitive to
      endocrine therapy. However, both primary and acquired resistance to endocrine therapy exists,
      and better combinations are constantly being explored to delay endocrine resistance and
      improve treatment outcome. Several known mechanisms of endocrine resistance have been
      proposed, and include deregulation of various components of the ER pathway itself,
      alterations in cell cycle and cell survival signaling molecules, and the activation of escape
      pathways that can provide tumors with alternative proliferative and survival stimuli.

      Endocrine blockade in breast cancer can be achieved by reducing the levels of estrogens
      through ovarian ablation (medical, surgical, or through radiation) in pre-menopausal women or
      with the administration of aromatase inhibitors in post-menopausal women. Direct inhibition
      of estrogen receptors can be achieved by administering selective estrogen receptor
      modulators, such as tamoxifen, or a pure estrogen receptor antagonist such as fulvestrant. In
      post-menopausal women with advanced breast cancer, current standard first-line endocrine
      therapy comprises of a reversible aromatase inhibitor such as letrozole or anastrozole. Other
      endocrine therapy options in advanced breast cancers include a irreversible aromatase
      inhibitor (exemestane), tamoxifen, megestrol acetate, and more novel combinations of an
      aromatase inhibitor with fulvestrant (combined estrogen blockade), exemestane combined with
      an mTOR inhibitor (everolimus), or letrozole combined with a CDK4/6 inhibitor (palbociclib).

      RET is an estrogen response gene, and preclinical studies have demonstrated cross talk
      between RET and ER. Significant interactions between RET and ERa pathways have been
      described, with increased response to estrogen stimulation observed in the presence of
      functional RET. RET is associated with resistance to tamoxifen and aromatase inhibitors, and
      increased RET expression has been demonstrated in hormone resistant cell lines and primary
      tumors. Combined anti-estrogen and anti-RET therapy in luminal breast cancer had a greater
      effect on cell growth than either therapy alone. The two classes of drugs have different
      mechanisms of action; a RET TKI reduced growth through induction of apoptosis, while anti-ERa
      reduced cell proliferation, forming the biologic basis for dual treatment. Dual therapy with
      tamoxifen and vandetinib, a RET inhibitor, resulted in greater reduction in tumor growth rate
      in MCF7 xenografts in mice. RET has been reported to be over-expressed in up to 75% of ER+
      breast cancers (n=20), compared to only 10% of ER-negative breast cancers (n=10) in a small

Trial Arms

Lenvatinib + LetrozoleExperimentalSingle agent lenvatinib daily continuously x 2 weeks, followed by Letrozole 2.5mg daily + lenvatinib x 12 weeks
  • Lenvatinib + Letrozole

Eligibility Criteria

        Inclusion Criteria:

          -  Female, age ≥18 years.

          -  Histologic or cytologic diagnosis of breast carcinoma.

          -  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.

          -  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 10^9/L Platelets ≥ 100 x


          -  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

          -  Signed informed consent from patient or legal representative.

        Exclusion Criteria:

          -  Prior treatment for locally advanced or metastatic breast cancer.

          -  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

          -  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
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rates of clinical response (complete and partial clinical response), including confidence intervals.
Time Frame:Post neoadjuvant chemotherapy (within 2-3 weeks after last dose of neoadjuvant chemotherapy)
Safety Issue:

Secondary Outcome Measures

Measure:Rates of pathological complete responses.
Time Frame:Post neoadjuvant chemotherapy (within 4-6 weeks after last dose of neoadjuvant chemotherapy)
Safety Issue:
Measure:Progression-free survival
Time Frame:2 and 5 year post neoadjuvant chemotherapy/time of surgery
Safety Issue:


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National University Hospital, Singapore

Last Updated

May 29, 2016