Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib

Study Overview
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Brief Summary
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To assess longitudinal changes in allele frequency of ESR1 mutation in plasma in patients treated with Fulvestrant plus palbociclib compared to tamoxifen plus palbociclib

Detailed Description
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The primary objectives are to assess longitudinal changes in allele frequency of ESR1 mutation in plasma in patients treated with Fulvestrant plus palbociclib compared to tamoxifen plus palbociclib. Patients with ER+ breast cancer who had 1 to 3 prior lines of endocrine therapy and up to one line of chemotherapy for MBC, excluding fulvestrant and tamoxifen, will be randomized in a 1:1 ratio to receive fulvestrant 500mg IM Q28 days with one extra dose on Day15 of the first cycle (as a loading dose) plus palbociclib 125mg/day PO on a 21 days on/7 days off schedule or tamoxifen 20mg PO daily plus palbociclib 125mg/day PO on a 21 days on/7 days off schedule.

Official Title
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Treatment of Metastatic Breast Cancer With Fulvestrant Plus Palbociclib or Tamoxifen Plus Palbociclib: A Randomized Pilot Trial With ESR1 Mutation Tested in Circulating Tumor DNA.

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Fulvestrant
* Drug: Tamoxifen
* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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For inclusion in the study subjects should fulfill the following criteria: Signed informed consent Patients must have histologically or cytologically confirmed invasive breast cancer that is ER+ (>1% staining) with radiographical or clinical evidence of metastatic disease a. Measurable and/or non-measurable disease Prior therapies: Patients must have previously received an aromatase inhibitor in the adjuvant, neo-adjuvant or metastatic setting. Patients must have previously received palbociclib in the adjuvant, neo- adjuvant or metastatic setting. If patient is currently taking palbociclib at time of screening for the trial they may continue taking palbociclib. The minimum duration of AI in the adjuvant setting is 2 years. There is no minimum duration of AI in the metastatic setting or neoadjuvant setting. Patients may have been previously treated with an mTOR inhibitor or other investigational agent in addition to an aromatase inhibitor. Prior treatment with tamoxifen is allowed in the adjuvant setting provided that it was followed by a minimum of 2 years of an AI. Brain metastasis is allowed if previously treated, stable and off steroids for a minimum of 56 days Age > 18 years Male or female breast cancer is allowed Patients may be pre- or post-menopausal; pre-menopausal patients must be on ovarian suppression and must be adequately suppressed on LHRH agonists with estradiol levels in the post-menopausal range a. Premenopausal patients cannot be pregnant and must agree to adequate birth control in addition to ovarian suppression. Agreement by the patient and/or partner to use highly effective, nonhormonal form of contraception or two effective forms of non-hormonal contraception. Contraception use should continue during the duration of study treatment and for at least 6 months after the last dose of study treatment. ECOG performance status 0-2 Adequate bone marrow function as indicated by the following, within 14 days of enrollment: ANC ≥ 1500 cells/mm3 Platelets ≥ 100,000 cells/ mm3 Hemoglobin ≥ 9 g/dL Adequate liver function, as indicated by the following, within 14 days of enrollment. Total bilirubin 1.5 upper limit of normal (ULN) AST 1.5 ULN ALT ≤ 2.5 ULN Alkaline phosphatase ≤ 2.5 ULN with the following exception; ALP ≤ 5× ULN in patients with bone metastases. Adequate hemostatic function as determined by PT, INR and aPTT < 1.5× ULN (unless on therapeutic coagulation, in which case the adequate level of anticoagulation will be determined by the investigator). Adequate renal function, as indicated by creatinine ≤ 1.5 ULN. Subjects should not enter the study if any of the following exclusion criteria are fulfilled Prior therapy exclusions: Prior therapy with fulvestrant Prior therapy with tamoxifen in the metastatic setting More than 3 prior lines of endocrine therapy in the metastatic setting More than one prior line of chemotherapy in the metastatic setting Washout of 2 weeks is required for aromatase inhibitors; washout of 4 weeks is required for, everolimus or other biological agents with the exception of Palbociclib. Patients must not be receiving any other investigational agent. Patients with symptomatic, untreated CNS metastases are not eligible. Patients may not have significant concurrent illness, infection, pregnancy or lactation Patients must not have a different active malignancy, except for skin basal cell carcinoma, skin squamous cell carcinoma and cervical intraepithelial neoplasia.

Ages Eligible for Study
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Minimum Age: 18 Years

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 |
| --- | --- |
| Active Comparator: Arm A<br>fulvestrant administered 500mg IM Q28 days plus palbociclib125mg/day PO on a 21 days on/7 days off schedule | Drug: Fulvestrant<br>* 500mg IM Q28 days<br>Drug: Palbociclib<br>* Tamoxifen or Fulvestrant plus palbociclib125mg/day PO on a 21 days on/7 days off schedule<br>|
| Active Comparator: Arm B<br>Tamoxifen is administered orally, at a dose of20mg PO Qdaily plus palbociclib125mg/day PO on a 21 days on/7 days off schedule | Drug: Tamoxifen<br>* 20mg PO Qdaily<br>Drug: Palbociclib<br>* Tamoxifen or Fulvestrant plus palbociclib125mg/day PO on a 21 days on/7 days off schedule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in allele frequency of ESR1 mutation | Assessment of longitudinal changes in allele frequency of ESR1 mutation (mt) in plasma in treated patients. ESR1 status will be assessed using ddPCR. Allelic frequency is quantified as compared to wild-type allele, independent of plasma volume. The range will be 0-100, with increased values indicating worse prognosis or disease progression. | Up to 6 months | 
| RNAseq for functionality of ESR1 | Assessment of the functionality of ESR1 in tumor biopsies collected prior to and following treatment as assessed by RNAseq. | Up to 6 months | 
| Number of participants with treatment-related adverse events | Treatment related adverse events will be assessed in all patients as assessed by CTCAE v4.0. This will be determined at the monthly visits. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | The duration of time from time of randomization to time of progression or death, whichever occurs first. Disease progression (PD) as defined by RECIST v1.1: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The progression of non-target lesions or the appearance of one or more new lesions is also considered progression. PFS for a subject without an event will be censored on the date of last tumor assessment. If an interval of 6 months passes without a tumor assessment, PFS will be censored at the time of the earlier tumor assessment, even if an event (progressive disease or death) is later observed. | Up to 5 years | 
| Objective Response Rate (ORR) | The proportion of patients with tumor size reduction per RECIST v1.1 ((Complete Response + Partial Response (PR) / all patients assessed for response). Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Up to 5 years | 
| Clinical benefit rate (CBR) | Clinical Benefit Rate is defined as the number of patients with Completed Response (CR)+Partial Response (PR)+ Stable Disease (SD) / all patients assessed for response per RECIST v1.1 . Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | Up to 5 years | 
| Assessment ESR1 status | Assessment of ESR1 status in plasma and biopsy samples. ESR1 status will be assessed using ddPCR. ESR1 status is quantified as compared to wild-type allele, independent of plasma volume. The range will be 0-100, with increased values indicating worse prognosis or disease progression. | Up to 5 years | 
| Changes in circulating levels of ESR1-mt | Assessment of longitudinal changes in circulating levels of ESR1-mt. The range will be 0-100, with increased values indicating worse prognosis or disease progression. | Up to 5 years | 
| Gene expression via cfRNA | Use of cfRNA to determine gene expression in AI resistant mutant ESR1 MBC. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ESR1 mutation