The PROMISE Study: Duavee in Women With DCIS

• ClinicalTrials.gov Identifier: NCT02694809
• Recruitment Status: Recruiting
• First Posted: March 1, 2016
• Last Update Posted: February 8, 2023
• Sponsor: Northwestern University
• Collaborators: National Cancer Institute (NCI); Pfizer; University of Chicago - Department for Cancer Research; University of California, San Francisco
• Information provided by (Responsible Party): Northwestern University

Tracking Information

• First Submitted Date: February 24, 2016
• First Posted Date: March 1, 2016
• Last Update Posted Date: February 8, 2023
• Study Start Date: January 2017
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 18, 2018)

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.

Original Primary Outcome Measures (submitted: February 24, 2016)

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.

Current Secondary Outcome Measures (submitted: June 18, 2018)

• 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.

Original Secondary Outcome Measures (submitted: February 24, 2016)

• 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.

Current Other Pre-specified Outcome Measures (submitted: June 18, 2018)

• 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.

Original Other Pre-specified Outcome Measures (submitted: February 24, 2016)

• 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.

Descriptive Information

• Brief Title: The PROMISE Study: Duavee in Women With DCIS
• Official Title: 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
• Brief Summary: 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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention

Condition

• Ductal Breast Carcinoma In Situ
• Postmenopausal

Intervention

• 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

Study Arms

• 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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 15, 2019): 160
• Original Estimated Enrollment (submitted: February 24, 2016): 130
• Estimated Study Completion Date: July 2024
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Women must have newly diagnosed histologically confirmed 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. Extent of DCIS in imaging per site institutional standard.

Note: After the patient has completed the study and the slides have been sent to NU, our pathologists will review the slides to confirm the diagnosis.

Note: 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.

Note: Women presenting with bilaterial DCIS are eligible but if both right and left DCIS are ER+, we will only accept tissue from the side with the largest area of DCIS based on imaging and pathology criteria outlined later in the protocol.

• DCIS must be ≥ 1cm based on extent of calcifications, presence of a mass on ultrasound OR enhancement on MRI OR DCIS must be ≥ 5mm of DCIS on one single core. Can be < 5mm if DCIS is identified on multiple cores (at least 2 cores)
• Women presenting after excision with positive margins are eligible. Ki-67, Cox-2, 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 salpingoopherectomy. Postmenopausal women of all races and ethnic groups are eligible to participate for this trial. Men are not eligible.

Note: women who have had a hysterectomy without a bilateral salpingoopherectomy may still be pre-menopausal. Confirmation of postmenopausal status is required for these patients and will be measured by testing levels of estradiol, progesterone and FSH (lab ranges per institutional standards). In addition, confirmation of postmenopausal status may be performed in any patient with unclear menopausal status per treating physician discretion.

• Women in the age range of ≥18-79 (inclusive)
• ECOG performance status ≤ 2 (Karnofsky ≥60%, see Appendix A).

• Patients must have normal organ and marrow function as defined below Leukocytes ≥3,000/mcL Platelets ≥100,000/mcL Hemoglobin ≥ 9g/dl Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) AST (SGOT) and ALT (SGPT)

  • 2.5 × institutional upper limit of normal Serum Creatinine OR Creatinine Clearance
  • 1.5 x ULN ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal (calculated with the Cockcroft-Gault Equation in EPIC)
• Patients must have the 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 ≥ 1 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 of invasive breast cancer Note: Patients who do not currently have a diagnosis of invasive breast cancer but who are planning to undergo additional standard of care testing to rule out a diagnosis of invasive breast cancer (such as future imaging or biopsy) are eligible. If the results of this standard of care testing later confirm that the subject has a diagnosis of invasive breast cancer, the subject should be withdrawn from the study at that time.
• Patients with recurrent ipsilateral DCIS

• Any of the following conditions, or a known history of any of the following:

  • deep venous thrombosis,
  • pulmonary embolism,
  • retinal vascular thrombosis,
  • any arterial thrombosis,- Known protein C, protein S, or anti-thrombin deficiency or other known thrombophilic disorders including stroke and myocardial infarction
• 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 CYP3A4 and UGT are ineligible. The wash out period for such drugs is a minimum of 7 days or 5 half-lives whichever is shorter. Refer to Appendix C.

Note: As this list is constantly evolving, if a medication is incorrectly documented as prohibited in this protocol, documentation from the site pharmacist to the contrary will be acceptable for the purposes of registration.

- 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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 79 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Study Coordinator; (312)695-1301; cancertrials@northwestern.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02694809
• Other Study ID Numbers: 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) )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Northwestern University
• Original Responsible Party: Same as current
• Current Study Sponsor: Northwestern University
• Original Study Sponsor: Same as current

Collaborators

• National Cancer Institute (NCI)
• Pfizer
• University of Chicago - Department for Cancer Research
• University of California, San Francisco

Investigators

• Principal Investigator: Swati Kulkarni, MD; Northwestern University

• PRS Account: Northwestern University
• Verification Date: February 2023