This is a single-centre study comprising two phases: a lead-in phase Ib and a phase II
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
- 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:
- SECONDARY ID:
- NCT ID:
|Lenvatinib + Letrozole||Lenvatinib + 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
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
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.
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
|Lenvatinib + Letrozole||Experimental||Single agent lenvatinib daily continuously x 2 weeks, followed by Letrozole 2.5mg daily + lenvatinib x 12 weeks|
- 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
- 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)
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.
- 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.
- 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|
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)|
Secondary Outcome Measures
|Measure:||Rates of pathological complete responses.|
|Time Frame:||Post neoadjuvant chemotherapy (within 4-6 weeks after last dose of neoadjuvant chemotherapy)|
|Time Frame:||2 and 5 year post neoadjuvant chemotherapy/time of surgery|
|Phase:||Phase 1/Phase 2|
|Lead Sponsor:||National University Hospital, Singapore|
May 29, 2016