Clinical Trials /

FES Imaging to Optimize Tamoxifen for Metastatic Breast Cancer

NCT04174352

Description:

Despite broad advancements in endocrine therapy for ERα+ breast cancer, resistance ultimately develops. A common driver of resistance are known ESR1 mutations that lead to constitutively active receptor signaling and transcriptional regulation that is always "turned on" despite the absence of estrogen. Patients with ESR1 mutations are expected to have decreased binding affinity for tamoxifen and thus may be underdosed on standard therapy. [18F]-fluoroestradiol Positron Emission Tomography/Computed tomography (FES-PET/CT) imaging is a novel functional imaging technique that can non-invasively measure ERα expression and inhibition in metastatic ERα+ breast cancer. The proposed a pilot study uses FES-PET/CT imaging to measure ERα blockade to determine the optimal dose of tamoxifen in patients with ESR1 mutations.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: FES Imaging to Optimize Tamoxifen for Metastatic Breast Cancer
  • Official Title: A Pilot Study of FES Imaging to Optimize Tamoxifen Dose for Metastatic Breast Cancer Patients With ESR1 Mutations

Clinical Trial IDs

  • ORG STUDY ID: UW19046
  • SECONDARY ID: 2019-0935
  • SECONDARY ID: A534260
  • SECONDARY ID: SMPH/MEDICINE/MEDICINE
  • NCT ID: NCT04174352

Conditions

  • ERα+ Breast Cancer
  • ESR1 Gene Mutation

Interventions

DrugSynonymsArms
TamoxifenTamoxifen Dose Levels

Purpose

Despite broad advancements in endocrine therapy for ERα+ breast cancer, resistance ultimately develops. A common driver of resistance are known ESR1 mutations that lead to constitutively active receptor signaling and transcriptional regulation that is always "turned on" despite the absence of estrogen. Patients with ESR1 mutations are expected to have decreased binding affinity for tamoxifen and thus may be underdosed on standard therapy. [18F]-fluoroestradiol Positron Emission Tomography/Computed tomography (FES-PET/CT) imaging is a novel functional imaging technique that can non-invasively measure ERα expression and inhibition in metastatic ERα+ breast cancer. The proposed a pilot study uses FES-PET/CT imaging to measure ERα blockade to determine the optimal dose of tamoxifen in patients with ESR1 mutations.

Trial Arms

NameTypeDescriptionInterventions
Tamoxifen Dose LevelsExperimentalThree participants will be enrolled to each dose level of oral tamoxifen (n = 12) Dose Level 1 = 20 mg daily Dose Level 2 = 80 mg daily Dose Level 3 = 160 mg daily Dose Level 4 = 200 mg daily Tamoxifen should be started within 14 days of the FES-PET/CT scan, at least 24 hours after FES injection. Participants will continue tamoxifen therapy until there is radiologic or clinical evidence of progressive disease or drug intolerance.
  • Tamoxifen

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically confirmed breast cancer that is metastatic or
             unresectable with the following:

               -  Estrogen receptor expression by immunohistochemistry > 10%

               -  ESR1 mutation identified using a Clinical Laboratory Improvement Amendments
                  (CLIA) certified assay via tumor biopsy tissue or circulating free DNA (cfDNA)

               -  human epidermal growth factor receptor 2 (HER2) negative

          -  Participants must have measurable disease as defined by RECIST 1.1 or evaluable
             bone-only disease with at least one lesion measuring 10 mm or greater in size.
             Participants with liver-only disease are not eligible due to the inherent hepatic
             uptake related to the radiopharmaceutical's hepatobiliary route of elimination.

          -  Participants must have received at least 1 prior line of non-tamoxifen containing
             endocrine therapy in the metastatic setting or have had progression within 12 months
             of adjuvant non-tamoxifen endocrine therapy.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (See Appendix A)

          -  Life expectancy of greater than 12 weeks.

          -  Ability to take oral medications.

          -  Informed consent: participant must be informed of the investigational nature of the
             study and must be able to sign a written informed consent.

          -  Participants with central nervous system (CNS) metastases must be stable after therapy
             for CNS metastases (such as surgery, radiation, or stereotactic radiosurgery) for at
             least 1 month.

          -  Participants must have adequate normal organ and bone marrow function as defined
             below:

               -  Absolute neutrophil count >/= 1,000/mcL

               -  Hemoglobin >/= 9.0 g/dL

               -  Platelets >/= 100,000/mcL

               -  Total bilirubin </= 1.5 x upper limit of normal (ULN)

               -  AST (SGOT)/ ALT (SGPT) </= 2.5 x ULN; </= 5 x ULN in the setting of metastatic
                  liver disease

               -  Creatinine </= 1.5 x ULN or creatinine clearance >/= 50 mL/min

        Exclusion Criteria:

          -  Participants must have received at least 1 prior line of non-tamoxifen containing
             endocrine therapy in the metastatic setting or have had progression either while
             taking or within 12 months of adjuvant non-tamoxifen endocrine therapy (i.e. on or
             within 12 months of an aromatase inhibitor).

          -  Prior chemotherapy, radiotherapy, targeted, immunotherapy or investigational therapy
             within 2 weeks or major surgery within 4 weeks of study enrollment or those who have
             not recovered (to grade ≤ 1 or baseline) from clinically significant adverse events
             due to agents administered more than 2 weeks earlier (alopecia and fatigue excluded).

          -  Participants must not be receiving an ER blocking endocrine therapy (includes
             fulvestrant, tamoxifen, toremifene, raloxifene) and must be off the agents for a
             minimum of 60 days to allow for adequate uptake of FES.

          -  History of allergic reactions attributed to compounds of chemical or biologic
             composition similar to those of tamoxifen or [18F]-fluoroestradiol.

          -  Peripheral neuropathy of severity greater than grade 1.

          -  Current optic nerve disorders, retinopathy, lattice degeneration, macular
             degeneration, retinal vascular disorder, or retinal tears of severity greater than
             grade 1.

          -  History of cerebellar disorders, ataxia, and uncontrolled seizures unless related to
             transient medical condition and in investigator's opinion is not an active medical
             issue.

          -  History of venous thrombosis/thromboembolic event, including pulmonary embolism and
             stroke.

          -  Have a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) ≥ 470msec
             or other factors that increase the risk of QT prolongation or arrhythmic events (e.g.,
             heart failure, chronic hypokalemia, family history of long QT interval syndrome).

          -  Are taking medications that are known to prolong the QT interval, unless they can be
             transferred to other medications within ≥ 5 half-lives prior to dosing or unless the
             medications can be properly monitored during the study. If equivalent medication is
             not available, QTcF should be closely monitored.

          -  Tamoxifen has demonstrated vaginal bleeding, birth defects and fetal loss in pregnant
             women. Tamoxifen use during pregnancy may have a potential long-term risk to the fetus
             of a Diethylstilbestrol syndrome (DES)-like syndrome. Women of childbearing potential
             (WOCP) must not be pregnant (confirmed by a negative urine/serum pregnancy test within
             14 days of tamoxifen treatment). In addition, a medically acceptable method of birth
             control must be used such as an intrauterine device (IUD), use of a double barrier
             method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or
             cream), or total abstinence during the study participation and for 3 months after last
             dose of study drug. Women who are postmenopausal for at least 1 year or surgically
             sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) are not
             considered to be WOCP.

          -  Ongoing treatment with other investigational agents. Participants cannot be receiving
             concomitant chemotherapy, radiotherapy, experimental therapy or any other therapy not
             otherwise outlined by the trial for the purposes of anti-cancer treatment.

          -  History of uterine malignancy unless participant has had hysterectomy with no evidence
             recurrent disease for ≥ 3 years from definitive therapy.

          -  Concurrent malignancy except for the following:

               -  Basal cell or squamous cell skin cancer

               -  In situ cervical cancer

          -  The following medications are contraindicated or must be used with caution.

               -  Contraindicated:

                    -  CYP2D6, CYP3A4, and CYP2C9 strong inhibitors

                    -  CYP2D6, CYP3A4, and CYP2C9 strong inducers

               -  Use with caution:

                    -  CYP2C9 sensitive substrates

                    -  CYP2D6 moderate inhibitors or inducers

                    -  CYP3A4 moderate inhibitors or inducers

        Note: Transdermal products designed for systemic delivery must be assessed for interaction
        potential. Topical products not designed to provide systemic delivery (including inhaled
        products, ophthalmologic products and transvaginal preparations) do not need to be
        considered.

        Contraindicated medications are not allowed. Participants taking these concurrent
        medications are ineligible unless they can discontinue or switch to alternative medications
        prior to initiation of study drug (at least 5 half-lives).

        Use with caution agents are permitted if a) discontinuation is not feasible or b) no
        acceptable alternatives are available as determined by the treating physician; however,
        caution should be used. Consider monitoring by symptoms, labs or drug levels and dose
        adjustments of the medication.

          -  Uncontrolled intercurrent clinically significant illness including, but not limited
             to, ongoing or active infection, symptomatic congestive heart failure, unstable angina
             pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
             limit compliance with study requirements.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of FES Blockade at each dose level to determine the Optimal Tamoxifen Dose
Time Frame:up to 6 weeks to compare baseline and treatment images
Safety Issue:
Description:Reduction in FES uptake will be described and analyzed by Fisher's exact test. Rates or proportion of responses at each dose level will be provided in data listings. If the SUVmax for all 5 target lesions have decreased by > 75% or all 5 lesions have SUVmax<1.5 on the second scan, then these participants will be prospectively defined as having complete FES blockade. If the SUVmax for any of the 5 lesions has not decreased by > 75% or if any new lesions arise with SUVmax ≥1.5, then these subjects will be defined as having incomplete FES blockade.

Secondary Outcome Measures

Measure:FES uptake at each dose level: SUVmax
Time Frame:up to 6 weeks to compare baseline and treatment images
Safety Issue:
Description:FES uptake will be quantified on 5 target lesions using standardized uptake value (SUV) measurements including SUVmax, SUVmean, SUVpeak, Tumor-to-Normal (T/N) tissue ratio, and Tumor-to-Blood Pool ratios.
Measure:FES uptake at each dose level: SUVmean
Time Frame:up to 6 weeks to compare baseline and treatment images
Safety Issue:
Description:FES uptake will be quantified on 5 target lesions using standardized uptake value (SUV) measurements including SUVmax, SUVmean, SUVpeak, Tumor-to-Normal (T/N) tissue ratio, and Tumor-to-Blood Pool ratios.
Measure:FES uptake at each dose level: Tumor-to-Normal tissue ratio
Time Frame:up to 6 weeks to compare baseline and treatment images
Safety Issue:
Description:FES uptake will be quantified on 5 target lesions using standardized uptake value (SUV) measurements including SUVmax, SUVmean, SUVpeak, Tumor-to-Normal (T/N) tissue ratio, and Tumor-to-Blood Pool ratios.
Measure:FES uptake at each dose level: Tumor-to-Blood Pool ratio
Time Frame:up to 6 weeks to compare baseline and treatment images
Safety Issue:
Description:FES uptake will be quantified on 5 target lesions using standardized uptake value (SUV) measurements including SUVmax, SUVmean, SUVpeak, Tumor-to-Normal (T/N) tissue ratio, and Tumor-to-Blood Pool ratios.
Measure:Objective Response Rate at each dose level
Time Frame:up to 6 months
Safety Issue:
Description:The objective response rate is the proportion of all participants with confirmed Partial Response or Complete Response according to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the start of treatment).
Measure:Safety: Number of Participants Experiencing Grade 3 or higher Adverse Events
Time Frame:Up to 21 days on treatment (up to 6 weeks on study)
Safety Issue:
Description:All grade 3-4 adverse events occurring between cycle 1, day 1 to cycle 2 day 1 and at least possibly related to therapy will be reviewed by the principal investigator prior to starting enrollment in the next dose cohort. If 2 or more of the 3 participants in any cohort experience grade 3-4 adverse events, then dose escalation will be halted.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Wisconsin, Madison

Last Updated

November 21, 2019