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The PROMISE Study: Duavee in Women With DCIS

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ClinicalTrials.gov Identifier: NCT02694809
Recruitment Status : Recruiting
First Posted : March 1, 2016
Last Update Posted : August 16, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Pfizer
Information provided by (Responsible Party):
Northwestern University

February 24, 2016
March 1, 2016
August 16, 2018
January 2017
August 2021   (Final data collection date for primary outcome measure)
Change in Ki-67 protein expression [ Time Frame: Up to 5 weeks ]
Evaluating if CE/BZA reduces proliferation as measured by Ki-67 protein expression. Change in Ki-67 between baseline and end of the intervention will be measured.
Change in Ki-67 protein expression [ Time Frame: Baseline to 4 weeks ]
Evaluating if CE/BZA reduces proliferation as measured by Ki-67 protein expression. Change in Ki-67 between baseline and end of the intervention (4 weeks) will be measured.
Complete list of historical versions of study NCT02694809 on ClinicalTrials.gov Archive Site
  • Expression of ERα [ Time Frame: Up to 5 weeks ]
    Determine if CE/BZA modulates expression of ERα.
  • Expression of progesterone receptor (PR) [ Time Frame: Up to 5 weeks ]
    Evaluate if CE/BZA modulates expression of PR
  • Expression of human epidermal growth factor receptor 2 (HER-2) [ Time Frame: Up to 5 weeks ]
    Determine if CE/BZA modulates expression of HER-2.
  • Epithelial markers of progression [ Time Frame: Up to 5 weeks ]
    Evaluate if CE/BZA modulates a previously validated set of epithelial markers of progression.
  • Expression of the stromal marker CD36 [ Time Frame: Up to 5 weeks ]
    Determine if TSECs will restore expression of the stromal marker CD36.
  • Repression of pro-tumorigenic ECM proteins [ Time Frame: Up to 5 weeks ]
    Determine if TSECs will repress pro-tumorigenic ECM proteins.
  • Repression of soluble factors [ Time Frame: Up to 5 weeks ]
    Determine if TSECs will repress soluble factors.
  • Quality of Life (QOL) [ Time Frame: Up to 5 weeks ]
    Evaluate if a short intervention with CE/BZA results in any difference in Quality of Life (QOL) as it relates to menopausal symptoms in postmenopausal women with DCIS.
  • Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire [ Time Frame: Up to 5 weeks ]
    Determine if a short intervention with CE/BZA has a favorable side effect profile compared with other endocrine therapy interventions using the validated Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire.
  • Change in ARCS signature [ Time Frame: Baseline to 4 weeks ]
    To assess whether CE/BZA alters markers associated with progression to invasive cancer (ARCS signature) in postmenopausal women with DCIS compared to placebo.
  • Change in QOL using MENQOL questionnaire [ Time Frame: Baseline to 4 weeks ]
    The difference in the MENQOL answers between baseline and end of the intervention will be evaluated.
  • Expression of estrogen-modulated genes in breast epithelium [ Time Frame: Up to 5 weeks ]
    Determine if CE/BZA alters expression of estrogen-modulated genes in breast epithelium.
  • Novel ER dependent-gene signatures in breast epithelium [ Time Frame: Up to 5 weeks ]
    Evaluate if CE/BZA elicits novel ER dependent-gene signatures in breast epithelium.
  • Anterior Gradient 2 (AGR2) [ Time Frame: Up to 5 weeks ]
    Demonstrate that CE/BZA does not upregulate Anterior Gradient 2 (AGR2), a marker of ERα agonist activity.
  • M2-type pro-tumorigenic macrophage signature [ Time Frame: Up to 5 weeks ]
    Determine if CE/BZA will modulate some aspects of immune function as measured by a switch to a M2-type pro-tumorigenic macrophage signature.
  • Immunosuppressive T cell signature [ Time Frame: Up to 5 weeks ]
    Determine if CE/BZA will modulate some aspects of immune function as measured by a switch to a an immunosuppressive T cell signature.
  • Estrogen-modulated genes in the breast stroma [ Time Frame: Up to 5 weeks ]
    Evaluate if a short intervention with CE/BZA alters expression of estrogen-modulated genes in the breast stroma.
  • Novel ER dependent-gene signatures in the breast stroma [ Time Frame: Up to 5 weeks ]
    Determine if a short intervention with CE/BZA elicits novel ER dependent-gene signatures in the breast stroma.
  • plasma concentrations of BZA [ Time Frame: Up to 5 weeks ]
    Evaluate if CE/BZA affects plasma concentrations of BZA in patients with the UGT1A1*28 gene polymorphism.
  • Change in CD36 [ Time Frame: Baseline to 4 weeks ]
    Changes in the stromal marker CD36 between baseline and the end of the intervention will be assessed in women with DCIS treated with CE/BZA compared to placebo.
  • Change in hormone receptor (ERa and PR) expression [ Time Frame: Baseline to 4 weeks ]
    To assess changes in hormone receptor (ERα and PR) expression in women with DCIS treated with CE/BZA compared to placebo.
  • Changes in global gene expression profiling using RNA sequencing [ Time Frame: Baseline to 4 weeks ]
    Using RNA sequencing to assess changes in global gene expression profiling in women with DCIS treated with CE/BZA when compared to placebo.
  • Identify possible polymorphisms [ Time Frame: Up to 4 weeks before surgery ]
    Peripheral blood will be collected at the baseline visit (preferably) or any time before surgery to identify possible polymorphisms that may affect the metabolism of CE/BZA.
 
The PROMISE Study: Duavee in Women With DCIS
A Large-scale Multicenter Phase II Study Evaluating the Protective Effect of a Tissue Selective Estrogen Complex (TSEC) in Women With Newly Diagnosed Ductal Carcinoma in Situ
The main purpose of this study is to determine if taking the study drug, conjugated estrogens/bazedoxifene (Duavee®) causes any changes in the proliferation markers within the breast tissue of the study subjects. The study drug is approved by the US Food and Drug Administration in healthy postmenopausal women to treat certain symptoms of menopause such as hot flashes. Since it is not approved in women with DCIS, its use in this study is experimental. This study will also look at whether taking the study drug causes any significant or undesirable side effects in women with DCIS. The researchers hope that this study will help them determine if taking the study drug is safe in women taking DCIS and if it can possibly reduce the risk of developing breast cancer in women with DCIS.

PRIMARY OBJECTIVES;

• To determine if CE/BZA reduces proliferation as measured by Ki-67 protein expression

Secondary Objectives:

  • To determine if CE/BZA modulates expression of ERα, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2).
  • To determine if CE/BZA modulates a previously validated set of epithelial markers of progression.
  • To determine if TSECs will restore expression of the stromal marker CD36 and repress pro-tumorigenic ECM proteins and soluble factors.
  • To determine if a short intervention with CE/BZA results in any difference in Quality of Life (QOL) as it relates to menopausal symptoms in postmenopausal women with DCIS.
  • To determine if a short intervention with CE/BZA has a favorable side effect profile compared with other endocrine therapy interventions using the validated Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire.

Exploratory Objectives

  • To determine if CE/BZA alters expression of estrogen-modulated genes and elicits novel ER dependent-gene signatures in breast epithelium
  • To demonstrate that CE/BZA does not upregulate Anterior Gradient 2 (AGR2), a marker of ERα agonist activity.
  • To determine if CE/BZA will modulate some aspects of immune function as measured by a switch to a M2-type pro-tumorigenic macrophage signature and an immunosuppressive T cell signature.
  • To determine if a short intervention with CE/BZA alters expression of estrogen-modulated genes and elicits novel ER dependent-gene signatures in the breast stroma.
  • To determine if CE/BZA affects plasma concentrations of BZA in patients with the UGT1A1*28 gene polymorphism.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive conjugated estrogens/bazedoxifene orally (PO) once daily (QD) for 28 +/- 7 days in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery.

ARM II: Patients receive placebo PO QD for 28 +/- 7 days in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery.

After completion of study treatment, patients are followed up for 30 days.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
  • Ductal Breast Carcinoma In Situ
  • Postmenopausal
  • Drug: Conjugated Estrogens/Bazedoxifene
    Given PO
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Other: Placebo
    Given PO
    Other Names:
    • placebo therapy
    • PLCB
    • sham therapy
  • Procedure: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
  • Experimental: Arm I (conjugated estrogens/bazedoxifene)
    Patients receive conjugated estrogens/bazedoxifene orally (PO) once daily (QD) for 28 +/- 7 days in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery.
    Interventions:
    • Drug: Conjugated Estrogens/Bazedoxifene
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Procedure: Quality-of-Life Assessment
    • Other: Questionnaire Administration
  • Placebo Comparator: Arm II (placebo)
    Patients receive placebo PO QD for 28 +/- 7 days in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Other: Placebo
    • Procedure: Quality-of-Life Assessment
    • Other: Questionnaire Administration
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
128
130
July 2022
August 2021   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Women must have newly diagnosed histologically confirmed estrogen receptor positive (ER+) DCIS scheduled to undergo surgical therapy; the pathology report (signed pathology report from attending pathologist) from each individual institution will be used to determine eligibility; (Note: after the patient has completed the study and the slides have been sent to Northwestern University [NU], our pathologists will review the slides to confirm the diagnosis)
  • DCIS suspicious for micro invasion is eligible on core biopsy; this is due to the fact that many these patients will not have invasion on final pathology
  • DCIS must be greater than or equal to 1 cm based on extent of calcifications, presence of a mass on ultrasound OR enhancement on magnetic resonance imaging (MRI)
  • DCIS must be at least 5 mm of DCIS on one single core; can be < 5 mm if DCIS is identified on multiple cores (at least 2 cores)
  • Women presenting after excision with positive margins are eligible; Ki-67, cyclooxygenase 2 (Cox-2), cyclin-dependent kinase inhibitor 2A (P-16), expression in immediately adjacent tissue is similar to what is found in DCIS Note: Positive margins are defined as DCIS present at the inked margin or DCIS <1mm from the margin.
  • Women must be postmenopausal (defined as no menstrual cycle for 12 months or surgical history of bilateral salpingo-oopherectomy); postmenopausal women of all races and ethnic groups are eligible to participate for this trial; men are not eligible
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 9 g/dl
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate [SGPT]) =< 2.5 × institutional upper limit of normal
  • Serum creatinine =< 1.5 x ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Patients ability to swallow oral medication
  • Ability to understand and the willingness to sign a written informed consent document and comply with all procedures

Exclusion Criteria:

  • Patients who are receiving any other investigational agents; a minimum of 4 weeks wash-out period is required for eligibility; please contact Principal Investigator, Dr. Swati Kulkarni for further clarification
  • Patients with a "currently active" second malignancy other than non-melanoma skin cancers; patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for >= 3 years
  • History of allergic reactions/hypersensitivity attributed to compounds of similar chemical or biologic composition to CE/BZA; (I.e. same class of drug as CE/BZA)

    • Current HRT, SERM or Aromatase Inhibitor (AI) use. If yes, the wash-out period is 30 days before diagnostic core needle biopsy.

Note: Local therapy (i.e. estrogen cream) will be permitted due to low systemic absorption of estrogen.

Note: if patient is registered prior to completed washout, diagnostic core needle biopsy date will need to be provided

  • Confirmed current or past diagnosis of invasive breast cancer
  • History of gynecologic malignancy that is estrogen dependent
  • Patients with recurrent ipsilateral DCIS
  • Active deep venous thrombosis, pulmonary embolism, retinal vascular thrombosis, and any arterial thrombosis including stroke and myocardial infarction or history of these conditions
  • Known protein C, protein S, or anti-thrombin deficiency or other known thrombophilic disorders
  • Unexplained/undiagnosed abnormal uterine bleeding (concern for undiagnosed endometrial cancer)
  • Women who are pregnant or lactating, CE/BZA may cause fetal harm when administered to a pregnant woman; if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus
  • Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) and uridine 5'-diphospho-glucuronosyltransferase (UGT) are ineligible; the wash out period for such drugs is a minimum of 7 days or 5 half-lives
  • Uncontrolled intercurrent 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
Sexes Eligible for Study: Female
18 Years to 75 Years   (Adult, Older Adult)
No
Contact: Study Coordinator (312)695-1301 cancertrials@northwestern.edu
United States
 
 
NCT02694809
NU 15B06
STU00202100 ( CTRP (Clinical Trial Reporting Program) )
NU 15B06 ( Other Identifier: Northwestern University )
P30CA060553 ( U.S. NIH Grant/Contract )
NCI-2016-00066 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Yes
Not Provided
Not Provided
Northwestern University
Northwestern University
  • National Cancer Institute (NCI)
  • Pfizer
Principal Investigator: Swati Kulkarni, MD Northwestern University
Northwestern University
August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP