Neoadjuvant Lenvatinib Combined With Letrozole in Hormone Receptor Positive Breast Cancer
|ClinicalTrials.gov 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
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.
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer||Drug: Lenvatinib + Letrozole||Phase 1 Phase 2|
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 :||Interventional (Clinical Trial)|
|Estimated Enrollment :||40 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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 Start Date :||September 2015|
|Estimated Primary Completion Date :||January 2018|
|Estimated Study Completion Date :||June 2018|
Experimental: Lenvatinib + Letrozole
Single agent lenvatinib daily continuously x 2 weeks, followed by Letrozole 2.5mg daily + lenvatinib x 12 weeks
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.
- 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) ]
- 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 ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02562118
|Contact: Soo Chin Lee||(65) 6779 firstname.lastname@example.org|
|National University Hospital||Recruiting|
|Singapore, Singapore, 119228|
|Contact: Soo Chin Lee (65) 6779 5555 email@example.com|
|Principal Investigator:||Soo Chin Lee||National University Hospital, Singapore|