Palbociclib and FES PET

Study Overview
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Brief Summary
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The purpose is to evaluate whether non invasive in vivo imaging of the estrogen receptor (ER) presence in metastatic breast cancer patient by means of 18F-fluoro-estradiol (FES) positron emission tomography (PET) can be used to predict treatment response to palbociclib plus letrozole. As ER expression predicts response to palbociclib in metastatic breast cancer patients the investigators hypothesize that lesions with low uptake on FES-PET will not respond to the combination of letrozole plus palbociclib.

Detailed Description
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To evaluate in a feasibility study whether low uptake on FES-PET at baseline is related to non response to letrozole plus palbociclib treatment. The investigators will perform this feasibility study in 15 patients with metastatic breast cancer, eligible for letrozole and palbociclib therapy. All patients will be treated with letrozole 2.5mg daily continuously throughout a 28-day cycle. This is combined with palbociclib 125 mg daily for 21 consecutive days followed by 7 days off treatment. At baseline all patients will have a FES PET scan. Currently the combination with palbociclib and letrozole has been approved by the FDA as initial endocrine-based therapy for postmenopausal women with ER positive HER2 negative advanced breast cancer. This is based on improved progression free survival with 10 months compared to endocrine therapy alone in both first and second line hormonal treatment for ER-positive metastatic breast cancer. In Europe, approval is expected late 2016. Therefore, in this study, all patients will receive a (presumably effective) treatment combination, that patients do not have standard access to in the Netherlands yet. In addition to the standard control visits to the clinic, two extra visits will be performed as part of the study: for screening and for the FES-PET scan. In the future, this study may potentially contribute to improved selection of patients for this combination treatment. This is of relevance in view of optimal treatment for individual patients, avoiding unnecessary toxicity and financial burden.

Official Title
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Early Identification of Patients Who Benefit From Palbociclib in Addition to Letrozole

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Palbociclib
* Device: FES PET
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, a subject must meet all of the following criteria: Patients with ER positive (i.e. >1% staining), HER2 negative metastatic breast cancer (preferably assessment on fresh metastasis biopsy, alternatively archival metastasis biopsy) Post-menopausal status defined as: Age ≥60 years Previous bilateral oophorectomy Age <60 years and amenorrhea for >12 months in the absence of interfering hormonal therapies (such as LH-RH agonists and ER-antagonists Age <60 years using ER antagonists should have amenorrhea for >12 months and FSH >24U/L and LH>14U/L Adequate bone marrow and organ function defined as follows: Absolute neutrophil count > 1.5 x 109/L Platelet count >100 x 109/L White blood cell count >3 x 109/L AST and ALT <3.0 x upper limit of normal (ULN) or <5 xULN in case of known liver metastases. Alkaline phosphatase <2.5 x ULN Total serum bilirubin < ULN or total bilirubin <3.0 x ULN with direct bilirubin within normal range in patients with Gilbert's Syndrome Creatinine clearance >50mL/min Lipase/amylase <1/5 x ULN Prothrombin time, partial thromboplastin time and INR <1.5 x ULN ECOG performance 0-2 Signed written informed consent Able to comply with the protocol Age ≥18 years Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: Life expectancy < 3 months Evidence of central nervous system metastases Presence of life-threatening visceral metastases Prior use of CDK4/6 inhibitor Use of estrogen receptor ligands including estrogens, fulvestrant or tamoxifen <6 weeks before study entry. Use of other anticancer therapy < 2 weeks prior to start with palbociclib Concurrent malignancy Active cardiac disease or a history of cardiac dysfunction Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of treatment that are known strong inducers or inhibitors of CYP3A4/5, known risk to prolong the QT interval or induce Torsades de Pointes, or narrow therapeutic window and are predominantly metabolized through CYP3A4/5.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib and FES PET<br>To evaluate whether low uptake on FES-PET at baseline is related to non-response to letrozole plus palbociclib treatment. | Drug: Palbociclib<br>* all patients will be treated with palbociclib, on a 3 weeks on, 1 week off cycle until progression<br>Device: FES PET<br>* all patients will have a FES PET at baseline<br>Drug: Letrozole<br>* all patients will be treated with Letrozole daily until progression<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The relation between low uptake on FES-PET to response per lesion |  | 8 weeks after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| quantitative FES-uptake and correlation with progression free survival |  | 6 months | 
| analysis of circulating tumor DNA and correlation with FES-PET results and progression free survival |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FES PET, Palbociclib