DCIS: RECAST Trial Ductal Carcinoma In Situ: Re-Evaluating Conditions for Active Surveillance Suitability as Treatment

Study Overview
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Brief Summary
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The goal of this trial is to see if active surveillance monitoring and hormonal therapy in patients diagnosed with ductal cell carcinoma in situ (DCIS), an early stage of breast cancer, can be an effective management of the disease. Participants will be asked to receive standard of care hormonal therapy or an investigational treatment. Participants will be asked to return for evaluation with MRI at three months and six months. Depending on the evaluation participants will have the option to continue on the treatment. If the evaluation suggests surgery is recommended, the participant will discontinue the study treatment and will undergo surgery. In addition to the treatment and MRI evaluation, participants will be asked to provide blood sample to understand their immune status, provide saliva sample for genetic testing, provide the study with a portion of the tissue or slides generated from tissue removed during surgery performed as part of their standard of care.

Detailed Description
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The goal of this trial is to see if active surveillance monitoring and hormonal therapy in patients diagnosed with Ductal cell Carcinoma In Situ (DCIS), an early stage of breast cancer, can be an effective management of the disease. The current management of most patients with DCIS involves surgical intervention with or without radiation, similar to more aggressive breast cancers. These treatments can come with some significant health effects.The main question this study aims to answer is: to determine whether novel endocrine therapy increases the fraction of patients who will be suitable for long-term active surveillance. Participants will be asked to take the study medication or receive standard of care hormonal therapy, depending on the treatment to which they have been randomized. Participants will be asked to return for evaluation with MRI at three months and six months. Depending on the evaluation, participants will have the option to continue on the treatment, with follow up evaluations of Mammogram and MRI at 6 month intervals. If the evaluation suggests surgery is recommended, the participant will discontinue the study treatment and will undergo surgery. In addition to the treatment and MRI evaluation, participants will be asked to: Provide blood sample to understand their immune status Provide saliva sample for genetic testing provide the study with a portion of the tissue or slides generated from tissue removed during surgery performed as part of their standard of care. Participants will be followed annually for 10 years.

Official Title
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DCIS: RECAST Trial -Ductal Carcinoma In Situ: Re-Evaluating Conditions for Active Surveillance Suitability as Treatment: a Breast Cancer Prevention Pilot Study

Conditions
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Ductal Carcinoma in Situ

Intervention / Treatment
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* Drug: Tamoxifen
* Drug: Exemestane
* Drug: Letrozole
* Drug: Anastrazole
* Drug: Testosterone + Anastrazole
* Drug: Elacestrant
* Drug: Z-endoxifen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female, at least 18 years old previous diagnosis of Hormone Receptor positive (HR+) DCIS (at least 50% ER or PR and 2+; biopsy will have been performed previously at diagnosis) with or without microinvasion Informed consent provided by the patient Willingness and ability to provide tumor samples for research Exclusion Criteria: Pregnant or actively breastfeeding women (must be documented by a pregnancy test during screening) History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent based on review of the medical record and patient history. Invasive carcinoma or identification of a mass on MRI that is subsequently biopsied and found to be invasive cancer Co-enrollment in clinical trials of pharmacologic agents requiring an Investigational new Drug Appilcation (IND) Ongoing treatment for DCIS other than what is specified in this protocol Uncontrolled intercurrent illness, including psychiatric conditions, that would limit compliance with study requirements. Medical history or ongoing gastrointestinal disorders potentially affecting the absorption of investigational agent and/or tamoxifen. Participants unable to swallow normally or unable to take tablets and capsules. Predictable poor compliance to oral treatment. Active inflammatory bowel disease or chronic diarrhea, known active hepatitis A/B/C*, hepatic cirrhosis, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection or banding procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: RECAST-DCIS is an open-label, multi-site platform study designed to offer women with Ductal cell Carcinoma In Situ (DCIS) 6 months of neo-adjuvant exposure to endocrine therapy with the intent of determining their suitability for long-term active surveillance without surgery.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: chemoprevention therapy per investigator choice<br>a. For premenopausal women: 20 mg or 5 mg tamoxifen orally b. for postmenopausal women: standard oral doses of AI of choice: exemestane 25 mg daily, letrozole 2.5 mg daily, or anastrozole 1 mg daily; or reduced exemestane dosing: 25 mg 3 times per week orally i. For postmenopausal women who are not tolerating an AI, low dose (5 mg) or standard dose (20 mg) of tamoxifen There is active follow up with MRI at baseline, 3 months, 6 months after treatment initiation, and every 6 months alternating MRI and mammogram for up to 5 years. Participants may continue treatment for up to 5 years. | Drug: Tamoxifen<br>* For premenopausal women: 20 mg or 5 mg tamoxifen orally for postmenopausal women: For postmenopausal women who are not tolerating an AI, investigators can change them to the low dose (5 mg) or standard dose (20 mg) of tamoxifen<br>Drug: Exemestane<br>* for postmenopausal women: standard oral doses of AI of choice: exemestane 25 mg daily, or reduced exemestane dosing: 25 mg 3 times per week orally<br>Drug: Letrozole<br>* for postmenopausal women: standard oral doses of AI of choice: letrozole 2.5 mg daily,<br>Drug: Anastrazole<br>* for postmenopausal women: standard oral doses of AI of choice: anastrozole 1 mg daily;<br>|
| Experimental: Testosterone + Anastrazole (T+Ai)<br>White solid pellet for subcutaneous insertion consisting of 100mg Testosterone and 4mg Anastrazole, an aromatase inhibitor. A cylindrical pellet (4.5mm diameter, 6.35mm diameter) is inserted subcutaneously in the upper outer gluteal region or iliac fossa every 3 months, with treatment up to 24 months. There is active follow up with MRI at baseline, 3 months, 6 months after treatment initiation, and every 6 months alternating MRI and mammogram for up to 5 years. Participants are followed for an additional 5 years. | Drug: Testosterone + Anastrazole<br>* Investigational drug. Both pre- and post- menopausal subjects. 100mg testosterone in combination with 4mg anastrazole administered subcutaneously every 3 months for up to 2 years.<br>* Other names: T+Ai;|
| Experimental: Elacestrant<br>Selective estrogen receptor degrader, Standard dose: 400mg PO with food once daily for treatment up to 36 months. Dose reduction of Elacestrant by up to 2 dose levels permitted depending on toxicity; 400 mg to 300 mg then 300 mg to 200 mg Participants requiring more than 2 dose reductions must discontinue treatment For patients on this arm there is active follow up with MRI at baseline, 3 months, 6 months after treatment initiation, and every 6 months alternating MRI and mammogram for up to 5 years. Participants are followed by for an additional 5 years. | Drug: Elacestrant<br>* Investigational drug. Both pre- and post- menopausal subjects. Elacestrant 400mg PO with food once daily up to 36 months.<br>|
| Experimental: Endoxifen<br>(Z)-endoxifen is the most active metabolite of the selective estrogen receptor modulator (SERM), tamoxifen. Standard dose: 10mg PO delayed release capsule of z-endoxifen once daily for treatment up to 36 months. same time with a glass of water either 1 hour before a meal or 2 hours after a meal and should not take with alcohol. For patients on this arm there is active follow up with MRI at baseline, 3 months, 6 months after treatment initiation, and every 6 months alternating MRI and mammogram for up to 5 years. Participants are followed for an additional 5 years. | Drug: Z-endoxifen<br>* Investigational drug. Both pre- and post- menopausal subjects. (z)-endoxifen 10mg delayed release capsule 1 hour before a meal or 2 hours after a meal once daily for up to 36 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients remaining on active surveillance at 7 months | Fraction of patients remaining on active surveillance at 7 months compared to control | 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine whether novel endocrine therapy increases the fraction of patients who will be suitable for long-term active surveillance as measured by the fraction of patients deemed to be low-risk for invasive cancer at 6 months compared to control | Fraction of patients categorized as low risk by MRI after 6 months of treatment--Measured by cases demonstrating endocrine responsiveness (Determined based on lesion and background or lesion alone or lack of lesion and minimal background) | 6 months | 
| To determine whether novel endocrine therapy increases the fraction of patients who will be suitable for long-term active surveillance as measured by the fraction of patients deemed to be low-risk for invasive cancer at 3 months compared to control | Fraction of patients categorized as low risk by MRI after 3 months of treatment--Measured by cases demonstrating endocrine responsiveness (Determined based on lesion and background or lesion alone or lack of lesion and minimal background) | 3 months | 
| Associate rate of progression to Invasive Ductal Carcinoma (IDC) with risk categorization after 6 months of treatment at 3 years | Correlation of low-risk categorization at 6 months with subsequent rate of Invasive Ductal Cell Carcinoma progression at 3 years | 3 years | 
| To assess the QoL impact of novel endocrine therapy compared to tamoxifen or Aromatase inhibitor (Ai) at standard or low dose using PROMIS and the FACT-ES composite score compared to control | Fraction of patients experiencing Minimum Important Difference in overall QOL measured by PROP-R statistics (PROMIS) and FACT-ES (functional assessment of cancer therapy- endocrine symptoms, a quality of life (QoL) assessment) | 6 months | 
| For those with an identified lesion on MRI imaging, determine whether neoadjuvant endocrine therapy decreases lesion volume (qualitative, quantitative) and whether that corresponds to the biologic type of Ductal cell carcinoma In Situ (DCIS) | Rate of reduction in focal lesions (mass and non-mass enhancement (NME) at 6 months and Rate of reduction in focal lesions using automated Functional Tumor Volume | 6 months | 
| To determine whether neoadjuvant endocrine therapy decreases automated background parenchymal enhancement (BPE and automated MRI density compared to Ai and Tamoxifen | % with contralateral reduction in qualitative and automated BPE and % reduction in contralateral breast density | 6 months | 
| Determine adherence to active surveillance protocol | Time to discontinuation of therapy (Tolerability of therapy) will be measured, and Adherence rates on each regimen, as well as PROP-R and FACT-ES score on each regimen will be measured. These assessments will be combined to evaluate efficacy and toxicity using a novel clinical benefit index. | 5 years | 
| Change in artificial intelligence predicted risk based on mammography | Correlation of BPE change with agent and compare to quantitative imaging density | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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active surveillance, hormone therapy, endocrine therapy