DNA-Guided Second Line Adjuvant Therapy For High Residual Risk, Stage II-III, Hormone Receptor Positive, HER2 Negative Breast Cancer

Study Overview
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Brief Summary
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A randomized, Phase II trial of circulating tumor DNA-guided second line Adjuvant therapy for high Residual risk, stage II-III, Estrogen Receptor positive, HER-2 negative breast cancer (DARE)

Detailed Description
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Surveillance population and ctDNA screening (up to 1000 patients): Clinically high risk, stage II-III, ER positive, HER2-, breast cancer patients who are currently receiving adjuvant endocrine therapy with an aromatase inhibitor or tamoxifen are eligible for ctDNA screening if they meet any one of the following criteria for high risk for recurrence: (i) predicted risk of distant recurrence or death equal to or greater than 15% calculated by PREDICT, RSPC, or CTS5 (for late recurrence), (ii) four or more positive axillary lymph nodes or ipsilateral supraclavicular involvement regardless of tumor size, (iii) primary tumor equal to or greater than 5 centimeters regardless of nodal status, (iv) patients with 1-3 positive nodes, regardless of tumor size are eligible if at least one of the following is also true: grade 3 histology, greater than or equal to 3 cm tumor size, high molecular risk score (i.e. Oncotype Dx Recurrence score(RS) > 26, MammaPrint high risk, EndoPredict > 4, Prosigna score > 60). In order to start ctDNA surveillance, patients must be currently receiving endocrine therapy and have completed at least 6 months, but no more than 7 years and with at least 3 more years of planned adjuvant endocrine therapy of treatment without distant recurrence. Prior adjuvant CDK4/6 therapy is allowed, but at least 12 months must have elapsed since completing CDK4/6 therapy and enrolling into ctDNA surveillance on this study. However, participants in the PENELOPE and PALLAS clinical trials are not eligible. For screening, patients will undergo Signatera testing during routine follow up clinic visits. The current ASCO/NCCN breast cancer practice guidelines recommend follow up visits every 4 to 6 months at the treating physician's discretion. The investigators anticipate that screening positivity rates will be the highest in patients between years 1-5 after initial diagnosis, based on the annual hazard rates of recurrence in ER positive breast cancer. However, since up to 50% of all recurrences occur after 5 years of follow-up, the investigators allow starting ctDNA screening up to 7 years after starting adjuvant endocrine therapy if a patient meets criteria for high risk.

Official Title
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A Randomized Phase II Trial Of Circulating Tumor DNA-Guided Second Line Adjuvant Therapy For High Residual Risk, Stage II-III, Hormone Receptor Positive, HER2 Negative Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Fulvestrant
* Drug: Adjuvant Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - 4.1.1. Stage II or III, HER2 negative, ER positive invasive breast cancer in male or female patients. For this study, ER positivity is defined as equal to or greater than 10% ER positivity by immunohistochemistry, regardless of progesterone receptor (PR) status. Patients with PR positive but ER negative cancer are not eligible. HER2 negative status is defined as per the ASCO/CAP 2018 practice guidelines. (i) if patients have synchronous bilateral ER+ breast cancer tissue from both sites should be submitted to Natera to perform ctDNA testing. (ii) patients with multifocal/multicentric tumors are eligible and the largest focus of cancer should be submitted for testing. All tumors must meet pathological criteria for HER2-and ER+ status. (iii) For. patients who received neoadjuvant therapy and have discordant ER and HER2 results between the diagnostic biopsy (pre-treatment) and surgical pathology (post neoadjuvant therapy), the ER+ and HER2- status of the post-treatment specimen determine eligibility. 4.1.2. Currently taking an aromatase inhibitor, or tamoxifen, as adjuvant endocrine therapy and have completed at least 6 months (i.e. 24 weeks), but no more than 7 years with 3 more years planned, of endocrine therapy. Patients may register for the screening phase of the study within the first 6 months of adjuvant endocrine therapy but the first ctDNA testing must occur at, or after, 6 months of endocrine therapy. (i) Adjuvant bisphosphonate therapy is allowed. (ii) LHRH analogues are required for premenopausal patients randomized to receive fulvestrant. 4.1.3. Clinical and pathological high risk for recurrence defined as any one of the following: (i) At least a 15% predicted risk of death within 10 years using ePREDICT V2.1 (https://breast.predict.nhs.uk/tool), or (ii) At least 15% or greater risk of distant metastasis within 10 years using RSPC, (https://tools.genomichealth.com/Tools/RSPCTool.aspx), or (iii) At least 15% or greater risk of distant metastasis within 10 years CTS5 (https://www.cts5-calculator.com) for patients who have completed a minimum of 4 years of adjuvant endocrine therapy, or (iv) Tumor size > 5 cm, regardless of lymph node status, or (v) 1-3 involved axillary lymph nodes and at least one of the following; Tumor size > 3 cm, High histological grade (e.g. grade 3). High genomic risk defined as Oncotype Dx Recurrence Score >26, EndoPredict score >4, Prosigna risk of recurrence score ≥ 60, or Mammaprint high risk. (vi) Patients who have received pre-operative (neoadjuvant) chemotherapy must have either: greater than or equal to 3 cm invasive residual cancer regardless of nodal status AND grade 3 disease or RS>26/MammPrint High/Prosigna high/Endopredict high status, or greater than or equal to 1 cm invasive residual cancer (ypT1c) and at least 1 positive lymph node (ypN+) AND grade 3 disease, or RS>26, or MammPrint High, or Endopredict high or Prosigna high status. 4.1.4. Patients must have FFPE tissue from the primary tumor available for submission to Natera to perform ctDNA assay (see Appendix B for tissue submission instructions). 4.1.5. Signed and dated informed consent, including willingness to be randomized to standard of care versus fulvestrant + palbociclib. 4.2 Inclusion and exclusion criteria for treatment randomization Inclusion criteria for randomization 4.2.1. ctDNA positivity by the Signatera assay, defined as 2 of the 16 cancer specific markers positive in plasma. 4.2.2. Patients with positive Signatera results obtained in the context of commercial testing, outside of the screening phase of this trial, are also eligible for randomization if they meet other eligibility criteria. 4.2.3. No evidence of metastatic disease on CT scan of the chest, abdomen and pelvis. If imaging, after review with a radiologist, is low probability for metastatic disease, patients may proceed to randomization. Patients with suspicious but inconclusive imaging results should undergo a diagnostic biopsy, if biopsy is negative patients are eligible for randomization. Patients with positive imaging that is conclusive of metastatic disease, or with biopsy proven metastatic disease, are not eligible for randomization. 4.2.4. Pre-menopausal women and male patients must be willing to use an adequate method of contraception for the duration of trial treatment and for 4 additional weeks after completion of treatment in the control arm, and for 2 years after the last dose of fulvestrant, if randomized into the experimental arm. Post-menopausal status is defined as: Documented bilateral oophorectomy. Age ≥ 60 years. Age < 60 years and amenorrhoeic for ≥ 12 consecutive months and FSH and estradiol levels in the post-menopausal range according to the institutional reference range for post-menopausal. Adequate contraception is defined as ONE highly effective form (i.e. abstinence, surgical sterilization through bilateral tubal ligation, vasectomy), or TWO effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository). - Abstinence is to be interpreted as true abstinence for heterosexual intercourse and therefore, periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus) are not considered highly effective. Exclusion Criteria 4.1.5. Prior or current treatment with fulvestrant, or current treatment with a CDK4/6 inhibitor, or treatment in the prior 12 months, or participants in the PENELOPE and PALLAS clinical trials. 4.1.6. Patients cannot start participation in another therapeutic clinical trial for breast cancer after enrollment in this trial. 4.1.7. Patients with current or past invasive cancer, other than breast cancer are not eligible, except: Adequately treated basal or squamous cell carcinoma of the skin are eligible. Cancer survivors of previously diagnosed invasive cancer, who were treated with a curative intent, have no evidence of disease recurrence for 5 years or more, and are considered low risk for future recurrence by the treating physician are also eligible. 4.1.8. Patients with a second HER2 positive or triple negative synchronous breast cancer are not eligible. Exclusion criteria for randomization 4.2.5. Patients with known contraindications to receive fulvestrant and palbociclib or those who are unable to tolerate these drugs are not eligible. Absolute neutrophil count less than <1000/mm3; 4.2.6. Any concurrent severe and uncontrolled medical condition that would, in the Investigator' opinion cause unacceptable safety risks or compromise compliance with the protocol including but not limited to: Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral medication (e.g. Crohn's disease, ulcerative diseases, uncontrolled chronic nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). History of pneumonitis, interstitial lung disease or pulmonary fibrosis. Known history of Human Immunodeficiency Virus (HIV) (testing is not mandatory). Known active Hepatitis B or Hepatitis C (testing is not mandatory). Females who are pregnant or breastfeeding. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting factor deficiency) that preclude the IM injections of fulvestrant or LHRH agonist as applicable. 4.2.7 Patients taking any CYPC3A4 strong inducers and inhibitors, that cannot be changed.
Sexes Eligible for Study
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All

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Palbociclib/Fulvestrant Combination | Drug: Palbociclib<br>* 4 week cycles<br>* Other names: IBRANCE;Drug: Fulvestrant<br>* 4 week cycles<br>* Other names: Faslodex;|
| Active Comparator: Arm B<br>Adjuvant Therapy | Drug: Adjuvant Therapy<br>* Standard of Care<br>* Other names: Standard of Care;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surveillance/ctDNA screening Phase | Primary objective of the ctDNA screening (surveillance) phase is to assess the incidence of ctDNA detection (i.e. ctDNA positivity) in patients with ER positive HER2 negative breast cancer who are receiving standard of care adjuvant endocrine therapy but remain high risk for recurrence. | enrollment | 
| Therapeutic Phase | Primary objective of the therapeutic randomized phase is to assess whether palbociclib plus fulvestrant improves relapse-free survival compared to standard of care adjuvant endocrine therapy in patients with ER+/HER2 negative breast cancer with detectable ctDNA in the plasma but without evidence of metastatic disease on imaging. | through study completion, an average of 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Objective 1: Feasibility- correlation between clinically apparent metastatic or local disease and positive ctDNA result. | Estimate proportion of patients who have clinically apparent metastatic or local disease (i.e. imaging positive) at the time of first positive ctDNA result. | enrollment | 
| Secondary Objective 2: Efficacy- assess the ability of positive ctDNA results to predict clinical relapse. | Assess the statistical correlation between ctDNA clearance, clinical relapse and the time to relapse in the control arm of the study. | through study completion, an average of 6 years | 
| Secondary Objective 3: Efficacy- assess whether ctDNA clearance is associated with improved relapse free survival and overall survival. | Assess the statistical correlation between ctDNA clearance, relapse free survival and overall survival in the treatment arm of the study. | through study completion, an average of 6 years | 
| Secondary Objective 4: Efficacy- assess the efficacy of the combination arm, palbociclib plus fulvestrant compared to the control arm. | Compare the statistical correlation between ctDNA clearance, relapse free survival and overall survival in the two arms of the study. | through study completion, an average of 6 years | 
| Secondary Objective 5: Safety and Tolerability- number of participants with treatment-related adverse event as assed by CTCAE V5.0. | To assess the tolerability and safety of treatments. | through study completion, an average of 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ctDNA, breast cancer, high residual risk