Clinical Trials /

Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation

NCT04432454

Description:

This is an open-label, multicenter, single-arm safety study evaluating the safety and tolerability of the lasofoxifene and abemaciclib combination for the treatment of pre- and postmenopausal women with locally advanced or metastatic ER+/HER2- breast cancer who have disease progression on first and/or 2nd lines of hormonal treatment for metastatic disease and have an ESR1 mutation.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2Breast Cancer With an ESR1 Mutation
  • Official Title: An Open-label, Multicenter Study Evaluating the Safety of Lasofoxifene in Combination With Abemaciclib for the Treatment of Pre- and Postmenopausal Women With Locally Advanced or Metastatic ER+/HER2Breast Cancer and Have an ESR1 Mutation ( ELAINEII )

Clinical Trial IDs

  • ORG STUDY ID: SMX 20-001
  • NCT ID: NCT04432454

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
Lasofoxifene and abemaciclib (VERZENIO (R).Treatment

Purpose

This is an open-label, multicenter, single-arm safety study evaluating the safety and tolerability of the lasofoxifene and abemaciclib combination for the treatment of pre- and postmenopausal women with locally advanced or metastatic ER+/HER2breast cancer who have disease progression on first and/or 2nd lines of hormonal treatment for metastatic disease and have an ESR1 mutation.

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalWomen who have locally advanced or metastatic ER+/HER2breast cancer and disease progression on first and/or 2nd lines of hormonal treatment for metastatic disease and have an ESR1 mutation
  • Lasofoxifene and abemaciclib (VERZENIO (R).

Eligibility Criteria

        Inclusion Criteria:

          1. Pre- or postmenopausal.

             Postmenopausal women are defined as:

               1. ≥ 60 years of age with no vaginal bleeding over the prior year, or

               2. < 60 years with "premature menopause" or "premature ovarian failure" manifest
                  itself with secondary amenorrhea for at least 1 year and follicle stimulating
                  hormone (FSH) and estradiol levels in the postmenopausal range according to
                  institutional standards, or

               3. surgical menopause with bilateral oophorectomy. Note: Premenopausal women who
                  meet all of the other entry criteria must be maintained on ovarian suppression
                  (such as Lupron) during the study and subjects counseled to use appropriate
                  contraception to prevent pregnancy.

          2. If possible, a biopsy of metastatic breast cancer tissue should be obtained to provide
             histological or cytological confirmation of ER+/HER2disease as assessed by a local
             laboratory, according to American Society of Clinical Oncology/College of American
             Pathologists guidelines, using slides, paraffin blocks, or paraffin samples. If a
             biopsy is not possible, the ER and HER2 status from the tissue obtained at the time of
             the original diagnosis must confirm that the subject is ER+ and HER2−.

          3. Locally advanced and/or metastatic breast cancer with radiological or clinical
             evidence of progression on the first or 2nd lines of hormonal therapy for metastatic
             disease. Progression may have occurred on no more than 2 of the following endocrine
             treatments for metastatic breast cancer: an aromatase inhibitor (AI) and/or
             fulvestrant either as monotherapy or in combination with any commercially approved
             CDKi; and/or the combination of fulvestrant and alpelisib; and/or tamoxifen; and/or
             the combination of exemestane/everolimus. (Note: before starting study treatment,
             subjects should have stopped any CDKi for at least 21 days)

          4. Subjects must have had no evidence of progression for at least 6 months during their
             first hormonal treatment for advanced breast cancer.

          5. At least one or more of the following ESR1 point mutations as assessed in cell-free
             circulating tumor DNA (ctDNA) obtained from a blood or tissue sample: Y537S, Y537C,
             D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. Note: the
             Sponsor's blood ctDNA assay must be used but tissue sequencing (if done) may be done
             by a validated commercial laboratory.

             Note: A positive ESR1 mutation in tissue or ctDNA using a validated commercial assay
             if done prior or at the time of disease progression is acceptable to meet this entry
             criteria. However, blood for ctDNA must still be obtained for genomic analyses using
             the sponsor's ctDNA assay.

          6. Locally advanced or metastatic breast cancer with either measurable (according to
             RECIST 1.1) or non-measurable lesions.

          7. Subjects may have received one cytotoxic chemotherapy regimen for metastatic disease
             as well as those who received one cytotoxic chemotherapy regimen in the neo-adjuvant
             or adjuvant setting prior to entry into the trial can be enrolled but must be free of
             all chemotherapy acute toxicity excluding alopecia and Grade 2 peripheral neuropathy
             before study entry. A washout period of at least 21 days is required between last
             chemotherapy dose and entry into the study.

          8. Stable breast cancer metastasis to the brain is allowed as long as the subject has
             received radiotherapy and not demonstrated any evidence of brain metastasis
             progression for at least 3 months after the completion of radiotherapy.

          9. ECOG performance score of 0 or 1.

         10. Adequate organ function as shown by:

               1. absolute neutrophil count (ANC) ≥ 1,500 cells/mm3

               2. platelet count ≥ 100,000 cells/mm3

               3. hemoglobin ≥ 8.0 g/dl

               4. ALT and AST levels ≤ 3 upper limit of normal (ULN) or ≤ 5 in the presence of
                  liver metastasis

               5. total serum bilirubin ≤ 1.5 X ULN (≤ 3 X ULN for subjects known to have Gilbert
                  Syndrome)

               6. alkaline phosphatase level ≤ 3 ULN

               7. creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault
                  formula

               8. International normalized ratio (INR) and activated partial thromboplastin (aPTT)
                  < 2.0 X ULN

         11. Able to swallow tablets.

         12. Able to understand and voluntarily sign a written informed consent before any
             screening procedures.

        Exclusion Criteria:

          1. Lymphangitic carcinomatosis involving the lung.

          2. Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.

          3. Radiotherapy within 30 days prior to entry into the study except in case of localized
             radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which
             can then be completed within 7 days prior to entry into the study. Subjects must have
             recovered from radiotherapy toxicities prior to entry into the study.

          4. Subjects with known inactivating RB1 mutations or deletions (Screening for RB1
             mutation is not required for entry).

          5. History of long QTC syndrome or a QTC of > 480 msec.

          6. History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6
             months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance
             are eligible as long as the DVT and/or PE occurred > 6 months prior to enrollment and
             there is no evidence for active thrombosis. The use of low-dose ASA is permitted.

          7. Subjects on concomitant strong CYP3A4 inhibitors such as clarithromycin,
             telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir,
             indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir.

          8. Subjects on strong and moderate CYP3A4 inducers such as amprenavir, barbiturates,
             carbamazepine, clotrimazole, dexamethasone, efavirenz, ethosuximide, griseofulvin,
             modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, chronic prednisone
             treatment, primidone, rifabutin, rifampin, rifapentine, ritonavir, topiramate.

          9. Any significant co-morbidity that would impact the study or the subject's safety.
             Since CDKi have reported the occurrence of interstitial lung disease (ILD), subjects
             with a history of ILD and those with severe dyspnea at rest or requiring oxygen
             therapy should not enter the study

         10. Subject has an active systemic bacterial or fungal infection (requiring intravenous
             [IV] antibiotics at the time of initiating study treatment).

         11. History of a positive human immunodeficiency virus (HIV) or hepatitis B virus (HBV)
             test. Screening is not required for enrollment.

         12. Subjects with hepatitis C virus (HCV) at Screening who still have a viral load.
             Subjects previously treated and achieved a HCV cure (no viral load) can be entered
             into the study

         13. History of malignancy within the past 5 years (excluding breast cancer), except basal
             cell or squamous cell carcinoma of the skin curatively treated by surgery, or
             early-stage cervical cancer.

         14. Positive pregnancy test (only if premenopausal).

         15. History of non-compliance to medical regimens.

         16. Unwilling or unable to comply with the protocol.

         17. Current participation in any clinical research trial involving an investigational drug
             or device within the last 30 days.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability of the combination of lasofoxifene and abemaciclib as measured by number of adverse events (AEs), severity of AEs and mortality due to AEs at every scheduled visit.
Time Frame:All subjects enrolled in the study will be treated until documented disease progression or until withdrawal for any reason. Safety and tolerability will be assessed from enrollment up to 24 months.
Safety Issue:
Description:AEs will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Up to 24 months
Safety Issue:
Description:PFS is defined as the time from the date of entry into the study to the earliest date of first documented progression or death due to any cause.
Measure:Clinical benefit rate (CBR)
Time Frame:24 weeks or longer
Safety Issue:
Description:
Measure:Objective response rate (ORR)
Time Frame:All subjects enrolled in the study will be treated until documented disease progression or until withdrawal for any reason. ORR will be assessed up to 24 months.
Safety Issue:
Description:
Measure:Duration of response (DoR)
Time Frame:DoR will be assessed up to 24 months.
Safety Issue:
Description:DoR is from the date of first documented response (CR or PR) to the date of first documented progression of disease or death due to any cause.
Measure:Time to response
Time Frame:Time to response will be assessed up to 24 months.
Safety Issue:
Description:From the date of entry into the study to the date of first documented response (CR or PR).
Measure:Steady-state pharmacokinetics (PK) sampling for lasofoxifene and abemaciclib concentrations as well as abemaciclib's 3 major metabolites of lasofoxifene and abemaciclib
Time Frame:Baseline and pre-dose at every visit starting at Visit 0 (Day 1) through Visit 4 (Week 8) and at the Final/ET visit if this occurred prior to Week 8
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sermonix Pharmaceuticals Inc.

Last Updated

June 12, 2020