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A Window of Opportunity Study of Pre-operative Endocrine Therapy With and Without Prometrium in Postmenopausal Women With Early Stage Breast Hormone Receptor Positive (HR+) Human Epidermal Receptor 2 Negative (HER2-) Breast Cancer. (WinPro)

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ClinicalTrials.gov Identifier: NCT03906669
Recruitment Status : Recruiting
First Posted : April 8, 2019
Last Update Posted : September 27, 2021
Sponsor:
Information provided by (Responsible Party):
Elgene Lim, St Vincent's Hospital, Sydney

Study Description
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Brief Summary:
A phase II randomised, open label study of pre-operative endocrine therapy with & without prometrium in postmenopausal women with early stage breast hormone receptor positive (HR+) human epidermal receptor 2 negative (HER2-) breast cancer.

Condition or disease Intervention/treatment Phase
Early-stage Breast Cancer Hormone Receptor Positive Tumor Drug: Letrozole Drug: Letrozole and Prometrium Drug: Tamoxifen and Prometrium Phase 2

Detailed Description:

There is bidirectional interplay between the progesterone receptor (PR) and oestrogen receptor (ER) in human breast cancers. There is evidence for a reprogramming of ER chromatin binding sites with 470 genes differentially regulated by dual treatment with estrogen plus progestogen compared to estrogen alone in breast cancer cell lines. Functionally, there was an additive anti-cancer effect with the addition of natural progesterone to endocrine therapy in preclinical breast cancer models.

This is a phase II multi-site, randomised, open-label, three-arm, study in 200 postmenopausal women with early-stage ER+, PR+, HER2-negative breast cancer. Eligible patients will be randomised (1:1:1) to receive 14 days of intervention with either letrozole 2.5mg PO daily (arm 1), letrozole 2.5mg + prometrium 300mg PO daily (arm 2) or tamoxifen 20mg + prometrium 300mg PO daily (arm 3), between diagnosis of breast cancer and definitive surgery.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Window of Opportunity Study of Endocrine Therapy With and Without Prometrium in Postmenopausal Women With Early Stage Hormone Receptor-positive Breast Cancer.
Actual Study Start Date : March 20, 2018
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Letrozole
Letrozole 2.5mg PO daily for 14 days between diagnosis of breast cancer and definite surgery
 Drug: Letrozole
PO daily for 14 days
Experimental: Letrozole and Prometrium
Letrozole 2.5mg PO daily and Prometrium 300mg PO daily for 14 days between diagnosis of breast cancer and definite surgery
 Drug: Letrozole and Prometrium
PO daily for 14 days
Experimental: Tamoxifen and Prometrium
Tamoxifen 20mg PO daily and Prometrium 300mg PO daily for 14 days between diagnosis of breast cancer and definite surgery
 Drug: Tamoxifen and Prometrium
PO daily for 14 days


Outcome Measures
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Primary Outcome Measures :
  1. Geometric mean suppression of proliferation marker Ki67 [ Time Frame: After two weeks of intervention, compared with baseline ]
    The geometric mean suppression of the centrally assessed proliferation marker Ki67, after two weeks of intervention, compared with baseline


Secondary Outcome Measures :
  1. Safety and tolerability: number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 2 years ]
    Safety and tolerability of combination therapy (NCI-CTCAE v4.0)


Other Outcome Measures:
  1. Define a gene set as a predictive biomarker for a reduction in Ki67 [ Time Frame: 4 years ]
    Expression of gene signature will be tested in the pre- and post-intervention tissues using the Nanostring nCounter system

  2. Evaluate changes in the apoptotic markers Bcl-2 and Caspase 3 in the tumors following intervention [ Time Frame: 4 years ]
    Immunohistochemistry of the pre and post intervention tissue samples

  3. Evaluate changes in ER, PR, AR, FoxA1, Cyclin D1 protein and mRNA expression in the tumors following intervention [ Time Frame: 4 years ]
    Immunohistochemistry of the pre and post intervention tissue samples


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed ER+ and PR+ breast cancer (defined as ≥10% positive staining cells)
  2. Histologically confirmed HER2-negative breast cancer (defined as IHC 0-1 and/or FISH/CISH <2.2)
  3. Tumour size ≥1 cm as measured by ultrasound and/or mammogram
  4. Ability to understand all patient information and informed-consent documents, written informed consent to participate in the trial, and to avail tissue and blood samples for research
  5. Aged 18 years or older

Exclusion Criteria:

  1. Women currently on hormone therapies, including hormone replacement therapy and oral contraceptive pill
  2. Locally advanced/inoperable and inflammatory breast cancer
  3. Planned for a mastectomy (due to increased risk of venous thromboembolism)
  4. Clinical evidence of metastatic disease
  5. Patients treated with other preoperative systemic therapies
  6. Nut allergy (prometrium contains peanut oil)
  7. Prior history of uterine cancer, deep vein thrombosis, pulmonary embolism or clotting disorder
  8. Women who are pregnant or breast-feeding
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03906669


Contacts
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Contact: Robert Kent +61293555611 SVHS.CancerResearch@svha.org.au

Locations
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Australia, New South Wales
St Vincent's Hospital Recruiting
Sydney, New South Wales, Australia, 2010
Contact: Robert Kent    +61293555611    svhs.cancerresearch@svha.org.au   
Sponsors and Collaborators
St Vincent's Hospital
Investigators
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Principal Investigator: Elgene Lim, MBBS FRACP PhD Garvan Research Institute
More Information
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Publications:

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Responsible Party: Elgene Lim, Associate Professor, St Vincent's Hospital, Sydney
ClinicalTrials.gov Identifier: NCT03906669    
Other Study ID Numbers: ACTRN1261000928213
First Posted: April 8, 2019    Key Record Dates
Last Update Posted: September 27, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Elgene Lim, St Vincent's Hospital, Sydney:
early stage breast cancer
prometrium
progesterone
post-menopausal
endocrine therapy
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Tamoxifen
Letrozole
Progesterone
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
 Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents
Progestins
Hormones