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Neoadjuvant Lenvatinib Combined With Letrozole in Hormone Receptor Positive Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02562118
Recruitment Status : Unknown
Verified May 2016 by National University Hospital, Singapore.
Recruitment status was:  Recruiting
First Posted : September 29, 2015
Last Update Posted : June 1, 2016
Eisai Co., Ltd.
Information provided by (Responsible Party):
National University Hospital, Singapore

Tracking Information
First Submitted Date  ICMJE September 8, 2015
First Posted Date  ICMJE September 29, 2015
Last Update Posted Date June 1, 2016
Study Start Date  ICMJE September 2015
Estimated Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 28, 2015)
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) ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 28, 2015)
  • Rates of pathological complete responses. [ Time Frame: Post neoadjuvant chemotherapy (within 4-6 weeks after last dose of neoadjuvant chemotherapy) ]
  • Progression-free survival [ Time Frame: 2 and 5 year post neoadjuvant chemotherapy/time of surgery ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Neoadjuvant Lenvatinib Combined With Letrozole in Hormone Receptor Positive Breast Cancer
Official Title  ICMJE 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
Brief Summary

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 study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE Drug: Lenvatinib + Letrozole
Single agent lenvatinib daily continuously x 2 weeks, followed by letrozole 2.5mg daily + lenvatinib x 12 weeks. Lumpectomy or mastectomy should be considered after completing 14 weeks of pre-operative lenvatinib + letrozole for curative intent in non-metastatic patients and for local control for patients with metastatic disease. If surgery is planned, it should preferably be performed within 2-12 weeks after completing neoadjuvant endocrine therapy, and after toxicities (if any) from the neoadjuvant endocrine therapy have resolved. If the patient is deemed inoperable after 14 weeks of lenvatinib + letrozole, a final biopsy will be obtained, and the patient discontinued from the study and treated as per standard clinical practice by the treating physician.
Study Arms  ICMJE Experimental: Lenvatinib + Letrozole
Single agent lenvatinib daily continuously x 2 weeks, followed by Letrozole 2.5mg daily + lenvatinib x 12 weeks
Intervention: Drug: Lenvatinib + Letrozole
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: September 28, 2015)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2018
Estimated Primary Completion Date January 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 10^9/L


  • 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.
  • 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 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Singapore
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT02562118
Other Study ID Numbers  ICMJE BR01/04/15
2015/00411 ( Other Identifier: NHG DSRB )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National University Hospital, Singapore
Study Sponsor  ICMJE National University Hospital, Singapore
Collaborators  ICMJE Eisai Co., Ltd.
Investigators  ICMJE
Principal Investigator: Soo Chin Lee National University Hospital, Singapore
PRS Account National University Hospital, Singapore
Verification Date May 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP