Clinical Trials /

Phase II Study of Single Agent Lenvatinib

NCT03168074

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Study of Single Agent Lenvatinib
  • Official Title: A Phase II Window-of-opportunity Study of Single Agent Lenvatinib in Estrogen Receptor Positive Early Stage Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: BR02/07/16
  • NCT ID: NCT03168074

Conditions

  • Breast Cancer

Interventions

DrugSynonymsArms
lenvatiniblenvatinib

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
lenvatinibExperimentalEligible patients will be treated with approximately 2 weeks of single agent lenvatinib (range 10-28 days, depending on the date of breast cancer surgery; last dose of lenvatinib to be administered no later than 48 hours before surgery in patients who are planned to receive ≤14 days lenvatinib, and no later than 120 hours before surgery in patients who are planned to receive 15-28 days lenvatinib).
  • lenvatinib

Eligibility Criteria

        Inclusion Criteria:

        Patients must fulfill ALL the following inclusion criteria

          -  Female ≥18 years

          -  Histological or cytological diagnosis of breast carcinoma

          -  No prior treatment for current breast carcinoma

          -  Scheduled for upfront definitive breast cancer surgery (breast conserving surgery or
             mastectomy with or without sentinel lymph node biopsy or axillary lymph node
             clearance)

          -  Estrogen receptor positive (>1%)

          -  Adequate bone marrow, renal and liver function

          -  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

          -  Able to swallow pills

          -  Able to sign informed consent

          -  Able to comply with study-related procedures

        Exclusion Criteria:

        Patients will be excluded from the study for any of the following reasons:

          -  Scheduled for neoadjuvant systemic therapy

          -  Concurrent administration of any other tumor therapy, including cytotoxic
             chemotherapy, hormonal therapy, and immunotherapy.

          -  Treatment within the last 28 days with any investigational drug.

          -  Major surgery within 28 days of study drug administration.

          -  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.

          -  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.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Biological effects of short-course single agent lenvatinib in estrogen receptor positive breast cancer using a window-of-opportunity design
Time Frame:after 10-28 days of single agent lenvatinib
Safety Issue:
Description:To evaluate Ki67 changes. The Ki-67 protein is a cellular marker for proliferation. It is strictly associated with cell proliferation. Ki67 has been shown to be a surrogate marker of biological activity and treatment response in estrogen receptor positive breast cancer treated with endocrine therapy.

Secondary Outcome Measures

Measure:Changes in the primary tumor dimensions
Time Frame:after 10-28 days of single agent lenvatinib
Safety Issue:
Description:to obtain the percentage change in primary breast tumor dimension measured by ultrasound
Measure:The proportion of subjects with tumor reduction
Time Frame:after 10-28 days of single agent lenvatinib
Safety Issue:
Description:to obtain the proportion of subjects with tumor reduction of at least 10%
Measure:Comparison of the clinical response of lenvatinib in RET negative versus RET positive, ER positive breast cancers
Time Frame:after 10-28 days of single agent lenvatinib
Safety Issue:
Description:To compare clinical response of lenvatinib in RET negative versus RET positive, ER positive breast cancers
Measure:Comparison in the overall average changes in biological effects of lenvatinib between RET negative and RET positive, ER positive breast cancers.
Time Frame:after 10-28 days of single agent lenvatinib
Safety Issue:
Description:: Comparison of the number of patients with Ki67 changes, histological response, apoptosis, RET and downstream targets such as AKT and ERK, between RET negative versus RET positive, ER positive breast cancers.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National University Hospital, Singapore

Last Updated