Neoadjuvant Response-guided Treatment of Slowly Proliferating Hormone Receptor Positive Tumors

Study Overview
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Brief Summary
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The purpose of this neoadjuvant trial is to evaluate efficacy and toxicity of the cdk 4/6 inhibitor palbociclib when added to standard endocrine treatment. Initially, patients receive endocrine treatment for 4 weeks. In case of decrease of proliferation (Ki67) patients are then randomized between either continuous endocrine therapy (arm A) or the same treatment with addition of palbociclib (arm B). Patients with no change of proliferation are allocated to endocrine treatment + palbociclib without randomization (arm C). During the 12-weekly treatment period, clinical and radiological evaluations are performed repeatedly. Switch between the treatment arms A and B is allowed in case of lack of response or due to toxicity. A translational subprotocol is a mandatory part of the study protocol, except for use of PET-CT evaluations.

Detailed Description
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Pre- or perimenopausal women are treated with tamoxifen, alternatively with an LHRH analogue in combination with an aromatase inhibitor (only women). Postmenopausal women receive an aromatase inhibitor.This treatment is given for 4 weeks. In cases with uncertain menopausal status (previous hysterectomy and equivocal gonadotropins), postmenopause age limit is defined as 55 years or older. Ki67 is determined by FNA or core biopsy before start and after 2 weeks of treatment. After the initial 4-week period, patients with signs of response in terms of decrease of Ki67 by ≥20% are randomized to endocrine treatment either alone or in combination with the cdk 4/6 inhibitor palbociclib (arm A and B). Patients with tumors with stable disease, defined as <20% decrease or increase of Ki67 and without radiological indication of tumor progression at the 4-week evaluation are offered continuous endocrine treatment with the addition of palbociclib (arm C). Dose regimen after 4 weeks of endocrine pretreatment: Arm A: Pre- or perimenopausal women are treated with tamoxifen, alternatively with an LHRH analogue in combination with an aromatase inhibitor (only women). Postmenopausal women receive an aromatase inhibitor. The preoperative treatment is continued for further 12 weeks, provided that re-evaluation after 6 and 10 weeks of the preoperative treatment does not indicate progression. Upon progression (PD), individualized management, preferentially surgery, is the primary option. Arm B: Patients receive the same endocrine treatment as in arm A together with palbociclib 125 mg orally days 1-21, followed by a 7-days rest period. The combined treatment is continued for further 12 weeks, if re-evaluation after 6 weeks, week 10 of the preoperative treatment, does not indicate progression. Upon progression (PD), individualized management, preferentially surgery, is the primary option. Arm C: Treatment according to the schedule as described for arm B. Postoperative chemotherapy is recommended to patients with either residual lymph node metastases >2mm (macro metastases) or primary tumor size >30mm in combination with Ki67>15%. Adjuvant endocrine treatment and radiotherapy is offered according to standard guidelines. Structured follow-up visits yearly for five years include reporting of persistent treatment-related toxicity, HRQoL, recurrence and death. All patients are recommended adjuvant endocrine treatment for at least 5 years. The trial contains also a translational subprotocol: PET-CT using FDG, confined to the chest, is performed before start of the first treatment period and after 10 weeks, i.e. 6 weeks after treatment allocation (functional imaging, optional). Core biopsies from the tumor are collected before start of the first treatment period and after 10 weeks, i.e. 6 weeks after treatment allocation. Further tissue samples are collected from the surgical specimen. Blood samples are collected repeatedly during the ongoing treatment and yearly follow-up. FNAs from metastases in case of recurrence during follow-up.

Official Title
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PREDIX Luminal A - Neoadjuvant Response-guided Treatment of Slowly Proliferating Hormone Receptor Positive Tumors. Part of a Platform of Translational Phase II Trials Based on Molecular Subtypes

Conditions
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Early-Stage Breast Carcinoma, Hormone Receptor Positive Tumor

Intervention / Treatment
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* Drug: Tamoxifen or Aromatase Inhibitor or Aromatase Inhibitor + goserelin
* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Female patients with non-lobular breast cancer confirmed by histology Tumor and blood samples available. Luminal A type confirmed by immunohistochemistry with ER and PR positive ≥50% and the proliferation marker Ki 67 <20% and not HER2 amplified Age older than 40 years Primary breast cancer >20mm without lymph node metastases Adequate bone marrow, renal, hepatic and cardiac functions and no other uncontrolled medical or psychiatric disorders LVEF >50% ECOG performance status 0-1 Exclusion Criteria: Metastases, including node metastases in the ipsilateral and/or contralateral thoracic region or in the mediastinum Other malignancy diagnosed within the last five years, except for radically treated basal or squamous cell carcinoma of the skin or CIS of the cervix Age ≤40 years Lobular carcinoma Patients in child-bearing age without adequate contraception Pregnancy or lactation Severe medical or psychiatric disorders where the study treatment or study procedures carry increased risk of deterioration of health status

Ages Eligible for Study
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Minimum Age: 41 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A: Endocrine treatment<br>Pre- or perimenopausal women are treated with tamoxifen, alternatively with an LHRH analogue in combination with an aromatase inhibitor (only women); postmenopausal women receive an aromatase inhibitor. The preoperative treatment is continued for further 12 weeks, provided that re-evaluation after 6 weeks, week 10 of the preoperative treatment, does not indicate progression. Upon progression (PD), individualized management, preferentially surgery, is the primary option | Drug: Tamoxifen or Aromatase Inhibitor or Aromatase Inhibitor + goserelin<br> <br> * Other names: Zoladex;|
| Experimental: B: Endocrine treatment + palbociclib<br>Patients receive the same endocrine treatment as in arm A together with palbociclib 125 mg orally days 1-21, followed by a 7-days rest period. The combined treatment is continued for further 12 weeks, provided that re-evaluation after 6 weeks, week 10 of the preoperative treatment, does not indicate progression. Upon progression (PD), individualized management, preferentially surgery, is the primary option | Drug: Tamoxifen or Aromatase Inhibitor or Aromatase Inhibitor + goserelin<br> <br> * Other names: Zoladex;Drug: Palbociclib<br> <br> * Other names: Ibrance;|
| Experimental: C: Endocrine treatment + palbociclib<br>Patients receive the same endocrine treatment as in arm A together with palbociclib 125 mg orally days 1-21, followed by a 7-days rest period. The combined treatment is continued for further 12 weeks, if re-evaluation after 6 weeks, week 10 of the preoperative treatment, does not indicate progression. Upon progression (PD), individualized management, preferentially surgery, is the primary option | Drug: Tamoxifen or Aromatase Inhibitor or Aromatase Inhibitor + goserelin<br> <br> * Other names: Zoladex;Drug: Palbociclib<br> <br> * Other names: Ibrance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical and Radiological Response | Clinical evaluations by use of calliper, radiological evaluations with mammography and ultrasound after 4, 10 and 16 weeks, PET-CT after 10 weeks of treatment, compared with baseline measurements | After 16 weeks of preoperative treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Evaluation of Tumor Response | Pathological signs of response, i.e. fibrosis, necrosis aso. | From date of surgery up to 4 weeks | 
| Disease-free Survival | Disease-free survival includes all events related to breast cancer, and death from any cause during the follow-up period | From date of surgery until 60 months past surgery | 
| Breast Cancer-specific Survival | Breast cancer-specific survival includes all events related to breast cancer and death caused by breast cancer during the follow-up period | From date of surgery until 60 months past surgery | 
| Overall Survival | Overall survival relates to death from any cause during the follow-up period | From date of surgery until 60 months past surgery | 
| Incidence of treatment-emergent adverse events [Safety and Tolerability] | Safety will be assessed using NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE) for reporting laboratory and non-laboratory toxicities. | From start of treatment until 28 days after termination of treatment. Delayed toxicity is reported until 60 months follow-up | 
| Health-related Quality of Life |  | From start of study treatment until termination, and then annually during the 60 months of postoperative follow-up period | 
| Biological characteristics of tumors exposed to targeted treatment of early breast cancer | Includes core biopsies and blood samples before start and after 10 weeks of treatment, collection of tumor samples from the surgical specimen at the date of operation, blood samples in connection with annual follow-up visits and FNA and blood samples in case of recurrence. Time frame for collection of biological samples from start of preoperative treatment until 60 months of follow-up post surgery. Planned analyses cover genomics (New Generation Sequencing) and proteomics | Before start and during treatment, at surgery, and then annually during the 60 months of postoperative follow-up period | 
| Immunohistochemical characteristics | Includes core biopsies before start and after 10 weeks of treatment, and collection of tumor samples from the surgical specimen at surgery | Before start, during treatment and at the date of operation | 
| Thymidine kinase (TK1) activity during study treatment | Includes repeated blood samples before start and after 4, 10 and 16 weeks of treatment | Before start and until termination of the preoperative treatment | 
| Drug metabolism during study treatment | Includes repeated blood samples after 4 and 10 weeks of treatment with the aim to compare intra- and inter-patient metabolism of endocrine treatment in relation to response | Four and ten weeks after start of the preoperative treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant Therapy, Cyclin-Dependent Kinase Inhibitor p16