Breast Cancer Clinical Trial
Official title:
A Phase II Window-of-opportunity Study of Single Agent Lenvatinib in Estrogen Receptor Positive Early Stage Breast Cancer
The Investigators hypothesize that single agent lenvatinib has biological activity in estrogen receptor positive breast cancer, and that the effects are more pronounced in patients with positive RET expression in the tumor.
Background and Rationale of Study:
A. RET and Endocrine Resistance in Breast Cancer RET is an estrogen response gene, and
preclinical studies have demonstrated cross talk between RET and ER. Significant
interactions between RET and ERα 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-ERα 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. Recently, the
investigators tested 94 archival breast cancer specimens from the National University
Hospital, Singapore and found RET over-expression (2-3+) to be present in 59% of ER negative
breast cancers (n=39) and 62% of ER positive breast cancers (n=55)
There is limited clinical experience in combining RET inhibitors with endocrine therapy in
breast cancer, with only one reported study using vandetanib. In this study, 127
post-menopausal metastatic breast cancer patients with hormone receptor-positive,
bone-predominant disease, were randomized to fulvestrant alone versus fulvestrant combined
with vandetanib. No differences in clinical benefit rate, progression-free survival, or
overall survival, were noted between the two treatment groups. Vandetanib, however, is a
less potent inhibitor of RET than lenvatinib. Lenvatinib has been granted orphan drug
designation for thyroid cancer by the United States Food and Drug Administration in 2013,
but is not being actively developed in breast cancer.
The investigators tested 9 ER+ breast cancer cell lines for RET expression using Western
blot, and identified 4 with high expression (BT474, MB361, HCC1419, UACC812), 2 with normal
expression (MCF7, CAMA1), and 3 with low expression (T47D, ZR-75-1, BT483). To evaluate the
effects of combining lenvatinib with endocrine therapy in ER+ breast cancer cell lines with
different RET expression, the investigators performed experiments using 6 cell lines,
including 2 with high RET expression (BT474, MB361), 2 with normal RET expression (MCF7,
CAMA1), and 2 with low RET expression (T47D, ZR-75-1). IC50 to tamoxifen and lenvatinib
alone was established for each cell line, followed by combination therapy at 3 different
doses for each drug. Cell apoptosis and proliferation was measured using caspase 3/7 and MTT
assays respectively. Preliminary experiments showed lenvatinib to have activity in ER
positive breast cancer cell lines, regardless of levels of RET expression. Lenvatinib was at
least additive with tamoxifen in all 6 ER positive breast cancer cell lines tested, with the
combination resulting in ≥50% cell kill compared to single agent tamoxifen in BT474, CAMA1,
and T47D cell lines. These pre-clinical observations suggest the potential role of
lenvatinib in combination with endocrine therapy in the treatment of ER positive breast
cancers.
Cells were seeded on 96-well plates and after 24 hours, the cells were treated with
tamoxifen and lenvatinib simultaneously at different doses (tamoxifen at 0, 1, or 5µM,
lenvatinib at 0, 5, 10 µM) and incubated for 72 hours. Cell viability was assessed using
CCK-8 assay.
B. Preliminary observation of clinical activity of single agent lenvatinib in hormone
receptor positive breast cancer
The investigators previously hypothesized that combining a RET inhibitor such as lenvatinib
with endocrine therapy may potentiate anti-tumor effects in hormone receptor positive breast
cancers. The investigators have recently initiated a study of lenvatinib + letrozole as
neoadjuvant therapy in hormone receptor positive breast cancer patients. Eligible patients
were treated with two weeks of single agent lenvatinib, followed by 12 weeks of lenvatinib +
letrozole. Two patients have been enrolled and the investigators observed tumor reduction of
10-15% on ultrasound after 2 weeks of single agent lenvatinib. To confirm these interesting
observations, the investigators intend to treat a larger cohort of patients with newly
diagnosed early stage breast cancer who are awaiting definitive breast cancer surgery with
approximately 2 weeks of single agent lenvatinib using a window-of-opportunity design, and
evaluate tumor response on ultrasound and histological changes from pre- and post-treatment
tumor biopsies. This design will allow the investigators to expand the target population for
rapid enrollment to achieve a quick signal on biological activity of lenvatinib in human
breast cancers in vivo.
;
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT04681911 -
Inetetamab Combined With Pyrotinib and Chemotherapy in the Treatment of HER2 Positive Metastatic Breast Cancer
|
Phase 2 | |
Terminated |
NCT04066790 -
Pyrotinib or Trastuzumab Plus Nab-paclitaxel as Neoadjuvant Therapy in HER2-positive Breast Cancer
|
Phase 2 | |
Completed |
NCT04890327 -
Web-based Family History Tool
|
N/A | |
Completed |
NCT03591848 -
Pilot Study of a Web-based Decision Aid for Young Women With Breast Cancer, During the Proposal for Preservation of Fertility
|
N/A | |
Recruiting |
NCT03954197 -
Evaluation of Priming Before in Vitro Maturation for Fertility Preservation in Breast Cancer Patients
|
N/A | |
Terminated |
NCT02202746 -
A Study to Assess the Safety and Efficacy of the VEGFR-FGFR-PDGFR Inhibitor, Lucitanib, Given to Patients With Metastatic Breast Cancer
|
Phase 2 | |
Active, not recruiting |
NCT01472094 -
The Hurria Older PatiEnts (HOPE) With Breast Cancer Study
|
||
Recruiting |
NCT06057636 -
Hypnosis for Pain in Black Women With Advanced Breast Cancer: A Feasibility Study
|
N/A | |
Recruiting |
NCT06049446 -
Combining CEM and Magnetic Seed Localization of Non-Palpable Breast Tumors
|
||
Recruiting |
NCT05560334 -
A Single-Arm, Open, Exploratory Clinical Study of Pemigatinib in the Treatment of HER2-negative Advanced Breast Cancer Patients With FGFR Alterations
|
Phase 2 | |
Active, not recruiting |
NCT05501769 -
ARV-471 in Combination With Everolimus for the Treatment of Advanced or Metastatic ER+, HER2- Breast Cancer
|
Phase 1 | |
Recruiting |
NCT04631835 -
Phase I Study of the HS-10352 in Patients With Advanced Breast Cancer
|
Phase 1 | |
Completed |
NCT04307407 -
Exercise in Breast Cancer Survivors
|
N/A | |
Recruiting |
NCT03544762 -
Correlation of 16α-[18F]Fluoro-17β-estradiol PET Imaging With ESR1 Mutation
|
Phase 3 | |
Terminated |
NCT02482389 -
Study of Preoperative Boost Radiotherapy
|
N/A | |
Enrolling by invitation |
NCT00068003 -
Harvesting Cells for Experimental Cancer Treatments
|
||
Completed |
NCT00226967 -
Stress, Diurnal Cortisol, and Breast Cancer Survival
|
||
Recruiting |
NCT06037954 -
A Study of Mental Health Care in People With Cancer
|
N/A | |
Recruiting |
NCT06019325 -
Rhomboid Intercostal Plane Block on Chronic Pain Incidence and Acute Pain Scores After Mastectomy
|
N/A | |
Recruiting |
NCT06006390 -
CEA Targeting Chimeric Antigen Receptor T Lymphocytes (CAR-T) in the Treatment of CEA Positive Advanced Solid Tumors
|
Phase 1/Phase 2 |