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Neoadjuvant Lenvatinib Combined With Letrozole in Hormone Receptor Positive Breast Cancer

Primary Purpose

Breast Cancer

Status
Unknown status
Phase
Phase 1
Locations
Singapore
Study Type
Interventional
Intervention
Lenvatinib + Letrozole
Sponsored by
National University Hospital, Singapore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring letrozole, lenvatinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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.

Sites / Locations

  • National University HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Lenvatinib + Letrozole

Arm Description

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)

Outcomes

Primary Outcome Measures

Rates of clinical response
Complete and partial clinical response, including confidence intervals.

Secondary Outcome Measures

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
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.

Full Information

First Posted
September 8, 2015
Last Updated
September 30, 2020
Sponsor
National University Hospital, Singapore
Collaborators
Eisai Co., Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT02562118
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Unknown status
Study Start Date
September 2015 (undefined)
Primary Completion Date
January 2021 (Anticipated)
Study Completion Date
June 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National University Hospital, Singapore
Collaborators
Eisai Co., Ltd.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief 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. 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 : 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer
Keywords
letrozole, lenvatinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Lenvatinib + Letrozole
Arm Type
Experimental
Arm Description
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)
Intervention Type
Drug
Intervention Name(s)
Lenvatinib + Letrozole
Intervention Description
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.
Primary Outcome Measure Information:
Title
Rates of clinical response
Description
Complete and partial clinical response, including confidence intervals.
Time Frame
2-3 weeks
Secondary Outcome Measure Information:
Title
Rates of pathological complete responses.
Description
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
Time Frame
4-6 weeks
Title
Progression-free survival
Description
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.
Time Frame
2 - 5 year

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Soo Chin Lee
Phone
(65) 6779 5555
Email
soo_chin_lee@nuhs.edu.sg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Soo Chin Lee
Organizational Affiliation
National University Hospital, Singapore
Official's Role
Principal Investigator
Facility Information:
Facility Name
National University Hospital
City
Singapore
ZIP/Postal Code
119228
Country
Singapore
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Soo Chin Lee
Phone
(65) 6779 5555
Email
soo_chin_lee@nuhs.edu.sg

12. IPD Sharing Statement

Citations:
PubMed Identifier
24526731
Citation
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.
Results Reference
background
PubMed Identifier
17538978
Citation
Semiglazov 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.
Results Reference
background

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Neoadjuvant Lenvatinib Combined With Letrozole in Hormone Receptor Positive Breast Cancer

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