Breast Cancer Clinical Trial
Official title:
A Phase II Randomized Trial of Lenvatinib Combined With Letrozole Versus Fulvestrant in Metastatic Estrogen Receptor (ER) Positive, HER2 Negative Breast Cancer, Who Have Progressed on First-line Aromatase Inhibitor + a CDK4/6 Inhibitor.
Based on the results of the phase Ib/II study, the investigators hypothesize that combining a RET inhibitor lenvatinib with endocrine therapy letrozole improves objective response and progression-free survival compared to fulvestrant alone in the second line setting in patients who have progressed on first line endocrine therapy incorporating a CDK4/6 inhibitor. Letrozole and fulvestrant are anti-hormonal drugs that have been proven to have activity and are considered standard therapies for hormone receptor positive breast cancer. The purpose of this study is to determine if the combination therapy of letrozole (an anti-hormonal drug) and lenvatinib (a targeted therapy), when compared to another anti-hormonal drug fulvestrant, is effective in patients with hormone receptor positive breast cancer. Preliminary studies have shown that approximately 50-60% of hormone receptor positive breast cancers over-express RET, and may therefore respond to treatment by a drug that blocks the RET pathway. An earlier study conducted at the National University Cancer Institute, Singapore (NCIS) on the combination of letrozole and Lenvatinib has shown promising results. Among patients in whom hormonal therapy and a CDK4/6 inhibitor no longer worked, about one-quarter of patients had meaningful disease control. The study also showed that patients tolerated the combination of Lenvatinib and letrozole well with manageable side effects. Based on the promising findings from the earlier study, this study seeks to compare the effectiveness of lenvatinib plus letrozole with another standard anti-hormone treatment drug called fulvestrant. In addition, investigators are studying how body reacts to the treatment as well as studying gene and protein changes in the tumour in response to treatment, which may in the future, help us tailor drug treatment for individual patients according to the patient's and/or the tumour's genetic or protein make-up.
Status | Recruiting |
Enrollment | 120 |
Est. completion date | August 2025 |
Est. primary completion date | August 2025 |
Accepts healthy volunteers | No |
Gender | Female |
Age group | 18 Years to 99 Years |
Eligibility | Inclusion Criteria: Patients may be included in the study only if patient meet all of the following criteria: - Female, age =>18 years. - Histologic or cytologic diagnosis of breast carcinoma. - Estrogen receptor positive (defined as =>1% on immunohistochemical staining) - Progressed on first-line palliative endocrine therapy plus CDK4/6 inhibitor as immediate prior line of endocrine therapy. Prior palliative letrozole is allowed. - Only one prior line of endocrine therapy in the metastatic setting. - No more than 1 prior line of chemotherapy in the metastatic setting. - Measurable disease by RECIST criteria. - 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 - Normal thyroid function on thyroid screen (fT4 and TSH). Patients who have thyroid dysfunction are eligible if thyroid function is optimally controlled. - 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, 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: Patients will be excluded from the study for any of the following reasons: - HER2 positive tumors. - Treatment within the last 30 days with any investigational drug. - Prior therapy with fulvestrant. - 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. - Non-healing wound. - Poorly controlled diabetes mellitus. - Second primary malignancy that is clinically detectable at the time of consideration for study enrollment. - Uncontrolled or symptomatic brain metastases, and/or brain metastases requiring steroids - History of significant neurological or mental disorder, including seizures or dementia. - Uncontrolled blood pressure (defined as persistent systolic BP >140 mmHg or diastolic BP>90mmHg) in spite of optimized regimen of antihypertensive medication - Presence of proteinuria defined as 24h urine collection of grade 2 and above (protein >1.0g/24h) - Significant cardiovascular impairment: history of congestive heart failure greater that New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of first dose of study drug, or cardiac arrhythmia requiring medical treatment at screening. - Bleeding or thrombotic disorders or gastrointestinal bleeding event or active hemoptysis or use of anticoagulants such as warfarin or similar agents requiring therapeutic INR monitoring, or subjects at risk of severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage / necrosis following Lenvatinib therapy. - Patients with baseline QTc interval >480ms that persists despite correction of electrolyte abnormalities and/or discontinuation of concomitant medications that are known to prolong QTc interval. |
Country | Name | City | State |
---|---|---|---|
Singapore | Nationa University Hospital | Singapore |
Lead Sponsor | Collaborator |
---|---|
National University Hospital, Singapore | Eisai Co., Ltd. |
Singapore,
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* Note: There are 14 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Progression-free survival (PFS) of patients treated on lenvatinib and letrozole compared to single agent fulvestrant | The PFS will be described using the Kaplan-Meier method and compared via logrank test. A total of 10 patients will be enrolled in the lead in portion of the study. If median PFS of the 10 patients is =4.5 months (upper limit of the 95% CI of median PFS to single agent fulvestrant in the retrospective study from NCIS), investigators will proceed to phase II randomized trial. If median PFS of the 10 patients is <3 months, study will not proceed to phase II randomized portion. If the median PFS of the 10 patients is between >3 months and <4.5 months, the study scientific committee will review and decide whether to proceed to the next part of trial. Interim analysis will be performed after 6 patients have been enrolled and the patient has been on study treatment for =6 months. If the PFS of all 6 patients is =4.5 months, investigators will move into the phase II randomized portion without the need to complete recruitment of all 10 patients into the lead-in phase II portion. |
30 months | |
Secondary | Overall objective response rate (ORR) measured by RECIST 1.1 criteria of patients treated with lenvatinib and letrozole compared to single agent fulvestrant | The ORR rates will be compared using the exact binomial test add quantified in terms of difference in proportion as well as relative risk estimate and the associated 95% confidence intervals. | 30 months | |
Secondary | Clinical benefit rate (CBR) measured by RECIST 1.1 criteria of patients treated with lenvatinib and letrozole compared to single agent fulvestrant | The CBR rates will be compared using the exact binomial test add quantified in terms of difference in proportion as well as relative risk estimate and the associated 95% confidence intervals. | 30 months | |
Secondary | Overall survival (OS) of patients treated with lenvatinib and letrozole compared to single agent fulvestrant | The OS curves will be described using the Kaplan-Meier method and compared via logrank test. | 30 months |
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