Breast CancerPhase 1/2NCT02562118
Neoadjuvant Lenvatinib Combined With Letrozole in Hormone Receptor Positive Breast Cancer
A Phase 1/2 study testing Lenvatinib + Letrozole in people with Breast Cancer, run by National University Hospital, Singapore at 1 site in Singapore.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Lenvatinib + Letrozole
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteSingapore
- Study dates
- 2 Oct 2015to Jun 2027
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read more
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
Read the detailed description
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
- To confirm the dose of lenvatinib that can be safely combined with letrozole in the lead-in Phase Ib part of the study.
- 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.
- 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
- 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.
- To identify biological predictors for treatment response to letrozole + lenvatinib in ER positive breast cancer using pharmacokinetics, pharmacogenetics, genomics and proteomics strategies.
- To compare the following parameters between RET positive versus RET negative, ER positive breast cancer:
- Part A :
- 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
- Conditions
- Breast Cancer
- Being tested
- Lenvatinib + Letrozole
- Keywords
- letrozole, lenvatinib
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lenvatinib + LetrozoleDrug
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 group | Role | What they receive |
|---|---|---|
| Lenvatinib + Letrozole | Experimental | Single agent lenvatinib daily continuously x 2 weeks, followed by Letrozole 2.5mg daily + lenvatinib x 12 weeks (for Part A) or continuous till progression or intolerability (Part B) Receives: Drug: Lenvatinib + Letrozole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Rates of clinical response
Complete and partial clinical response, including confidence intervals.
Measured: 2-3 weeks
Secondary outcomes (2)
Rates of pathological complete responses.
A pathological complete responder is defined as any patient who demonstrates no histological evidence of invasive tumor in the primary breast site as well as in resected axillary lymph nodes
Measured: 4-6 weeks
Progression-free survival
Time to documented disease progression is defined as the time from the date of study enrollment to the first date of documented disease progression. Time to documented disease progression will be censored at the date of death for patients who have not had documented disease progression. For patients who are still alive at the time of analysis and who have not had documented disease progression, time to documented disease progression will be censored at the date of the last follow-up visit.
Measured: 2 - 5 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Sep 2015 (estimated)
- Study start2 Oct 2015
- Primary completionJan 2027 (estimated)
- Study completionJun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Collaborators
- Eisai Co., Ltd.
- Responsible party
- Sponsor
- Investigators
- Soo Chin Lee, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02562118
- Sponsor's protocol ID
- BR01/04/15
- Other IDs
- 2015/00411, 2015
- Status last verified
- Sep 2025
- First submitted
- 8 Sep 2015
- Last updated
- 25 Sep 2025
- Results posted
- No
- Data monitoring committee
- No
Publications
Spanheimer PM, Park JM, Askeland RW, Kulak MV, Woodfield GW, De Andrade JP, Cyr AR, Sugg SL, Thomas A, Weigel RJ. Inhibition of RET increases the efficacy of antiestrogen and is a novel treatment strategy for luminal breast cancer. Clin Cancer Res. 2014 Apr 15;20(8):2115-25. doi: 10.1158/1078-0432.CCR-13-2221. Epub 2014 Feb 13.
PubMed 24526731Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, Melnikova OA, Paltuev RM, Kletzel A, Berstein LM. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007 Jul 15;110(2):244-54. doi: 10.1002/cncr.22789.
PubMed 17538978
Study at a glance
From the registry record, last updated by the sponsor on 25 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02562118
- Acronym / sponsor ID
- BR01/04/15
- Conditions
- Breast Cancer
- Keywords
- letrozole, lenvatinib
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Collaborators
- Eisai Co., Ltd.
- Study start
- 2 Oct 2015 (actual)
- Primary completion
- Jan 2027 (estimated)
- Study completion
- Jun 2027 (estimated)
- First posted
- 29 Sep 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
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
- To confirm the dose of lenvatinib that can be safely combined with letrozole in the lead-in Phase Ib part of the study.
- 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.
- 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
- 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.
- To identify biological predictors for treatment response to letrozole + lenvatinib in ER positive breast cancer using pharmacokinetics, pharmacogenetics, genomics and proteomics strategies.
- To compare the following parameters between RET positive versus RET negative, ER positive breast cancer:
- Part A :
- 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
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Lenvatinib + Letrozole | Experimental | Drug: Lenvatinib + LetrozoleSingle agent lenvatinib daily continuously x 2 weeks, followed by Letrozole 2.5mg daily + lenvatinib x 12 weeks (for Part A) or continuous till progression or intolerability (Part B) |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 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.
Key exclusion criteria (13 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Lenvatinib + LetrozoleSingle 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. | Drug | Lenvatinib + Letrozole |
Primary outcome
Rates of clinical response
Time frame: 2-3 weeks
Complete and partial clinical response, including confidence intervals.
2 secondary outcomes
Rates of pathological complete responses.
Time frame: 4-6 weeks
Progression-free survival
Time frame: 2 - 5 year
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Sep 2025.
- Background: PubMed 24526731Spanheimer PM, Park JM, Askeland RW, Kulak MV, Woodfield GW, De Andrade JP, Cyr AR, Sugg SL, Thomas A, Weigel RJ. Inhibition of RET increases the efficacy of antiestrogen and is a novel treatment strategy for luminal breast cancer. Clin Cancer Res. 2014 Apr 15;20(8):2115-25. doi: 10.1158/1078-0432.CCR-13-2221. Epub 2014 Feb 13.
- Background: PubMed 17538978Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, Melnikova OA, Paltuev RM, Kletzel A, Berstein LM. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007 Jul 15;110(2):244-54. doi: 10.1002/cncr.22789.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Soo Chin Lee principal investigator
National University Hospital, Singapore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Lenvatinib + Letrozole in people with Breast Cancer, run by National University Hospital, Singapore at 1 site in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 25 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rates of clinical response (time frame: 2-3 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02562118, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2025.