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Neoadjuvant Response-guided Treatment of Luminal B-type Tumors and Luminal A-type Tumors With Node Metastases (PREDIX LumB)

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ClinicalTrials.gov Identifier: NCT02603679
Recruitment Status : Recruiting
First Posted : November 13, 2015
Last Update Posted : September 8, 2016
Sponsor:
Information provided by (Responsible Party):
Thomas Hatschek, Karolinska University Hospital

Brief Summary:
The purpose of this neoadjuvant trial is to evaluate efficacy and toxicity of chemotherapy using weekly paclitaxel (arm A) versus the combination of the cdk 4/6 inhibitor palbociclib and standard endocrine treatment (arm B). After 12 weeks treatment is switched crossover. During the 24-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. Postoperatively, patients receive three 3-weekly courses of chemotherapy with a combination of epirubicin and cyclophosphamide.

Condition or disease Intervention/treatment Phase
Early-Stage Breast Carcinoma Estrogen Receptor Positive Tumor Drug: Paclitaxel Drug: Tamoxifen + Palbociclib Drug: Aromatase Inhibitor + Palbociclib Drug: Goserelin + Aromatase Inhibitor + Palbociclib Phase 2

Detailed Description:

Patients are randomized to either weekly treatment with paclitaxel (arm A) or endocrine treatment in combination with palbociclib (arm B) for 12 weeks. Choice of endocrine treatment is for pre- and perimenopausal women and all men tamoxifen 20 mg daily, alternatively for women in this age cohort, an LHRH analogue in combination with an aromatase inhibitor, for all postmenopausal women treatment with an aromatase inhibitor. The aromatase inhibitors to be used according to local practice are anastrozole 1 mg daily, exemestane 25 mg daily, or letrozole 2.5 mg daily. Pre- or perimenopausal women and all men are treated with tamoxifen, alternatively with an LHRH analogue in combination with an aromatase inhibitor (only women). Postmenopausal women receive an aromatase inhibitor.

After 12 weeks, patients without signs of disease progression (PD) are switched to either endocrine treatment in combination with palbociclib (arm A) or weekly treatment with paclitaxel (arm B) for 12 weeks. Postoperatively, patients receive three 3-weekly courses of chemotherapy with a combination of epirubicin and cyclophosphamide.

Before start, after 6, 12, 18 and 24 weeks of treatment, radiological assessments of tumor size are performed using mammography and ultrasound alt. MRI breast; PET-CT, confined to the breast and regional lymph nodes, before start, after 12 and 24 weeks, blood tests before start, after 1 week, 12, 18 and 24 weeks. Physical examinations are performed before start and then four-weekly after weeks 4, 8, 12, 16, 20 and 24 weeks of treatment.

In case of disease progression during ongoing study treatment, individualized management in the patient's best interest must be considered, in which case surgery is the primary option.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PREDIX Luminal B - Neoadjuvant Response-guided Treatment of ER Positive Tumors With High Proliferation or Low Proliferation With Metastatic Nodes. Part of a Platform of Translational Phase II Trials Based on Molecular Subtypes
Study Start Date : February 2015
Estimated Primary Completion Date : June 2018
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: A: Weekly Paclitaxel
Patients receive weekly paclitaxel 80mg/m2, eventually dose-adjusted in relation to side effects, for a 12-week period. Thereafter, treatment is switched to endocrine treatment in combination with palbociclib. Pre- or perimenopausal women and all men are treated with tamoxifen, alternatively with an LHRH analogue in combination with an aromatase inhibitor (only women); postmenopausal women receive an aromatase inhibitor together with palbociclib 125 mg orally days 1-21, followed by a 7-days rest period, repeated twice during the second 12-week period
Drug: Paclitaxel
Any brand of paclitaxel may be used, excluding nab-paclitaxel

Experimental: B: Tamoxifen + Palbociclib
Pre- or perimenopausal women and all men are treated with tamoxifen together with palbociclib 125 mg orally days 1-21, followed by a 7-days rest period, repeated twice during a 12-week period. Thereafter, treatment is switched to weekly paclitaxel 80mg/m2, eventually dose-adjusted in relation to side effects, for further 12 weeks.
Drug: Tamoxifen + Palbociclib
Any brand of tamoxifen may be used
Other Names:
  • Tamoxifen
  • Ibrance

Experimental: B: Aromatase Inhibitor + Palbociclib
Postmenopausal women receive an aromatase inhibitor together with palbociclib 125 mg orally days 1-21, followed by a 7-days rest period, repeated twice during a 12-week period. Thereafter, treatment is switched to weekly paclitaxel 80mg/m2, eventually dose-adjusted in relation to side effects, for further 12 weeks.
Drug: Aromatase Inhibitor + Palbociclib
Any brand of letrozole, anastrozole or exemestane may be used
Other Names:
  • Letrozole
  • Anastrozole
  • Exemestane
  • Ibrance

Experimental: B: Goserelin + Aromatase Inhibitor + Palbociclib
Pre- or perimenopausal women may be treated with goserelin and an aromatase inhibitor together with palbociclib 125 mg orally days 1-21, followed by a 7-days rest period, repeated twice during a 12-week period. Thereafter, treatment is switched to weekly paclitaxel 80mg/m2, eventually dose-adjusted in relation to side effects, for further 12 weeks.
Drug: Goserelin + Aromatase Inhibitor + Palbociclib
Any brand of letrozole, anastrozole or exemestane may be used
Other Names:
  • Zoladex
  • Letrozole
  • Anastrozole
  • Exemestane
  • Ibrance




Primary Outcome Measures :
  1. Radiological Objective Response Rate after Completion of the First 12-week Period of Primary Medical Treatment [ Time Frame: Start of treatment until 12 weeks of treatment ]
    Radiological response by use of mammography and ultrasound, alternatively MRI of the breast, if mammography/ultrasound does not allow for objective measurements of the primary tumor. Clinical measurements using calliper, if the tumor is palpable and tumor size cannot be estimated by radiological methods


Secondary Outcome Measures :
  1. Pathological Objective Response Rate [ Time Frame: From the date of surgery up to 4 weeks after surgery ]
    Presence/abscense of residual tumor in mm, fibrosis and other signs of response by histology

  2. Sequencing of Chemotherapy versus Endocrine Treatment plus Palbociclib in relation to Radiological Objective Response Rate after Completion of the 24-week Period of Primary Medical Treatment [ Time Frame: From start of treatment until termination of the preoperative treatment after 24 weeks ]
    Radiological response by use of mammography and ultrasound, alternatively MRI of the breast, if mammography/ultrasound does not allow for objective measurements of the primary tumor. Clinical measurements using calliper, if the tumor is palpable and tumor size cannot be estimated by radiological methods

  3. Disease-Free Survival [ Time Frame: From date of surgery until 60 months past surgery ]
    Disease-free survival includes all events related to breast cancer, and death from any cause during the follow-up period

  4. Breast Cancer-Specific Survival [ Time Frame: From date of surgery until 60 months past surgery ]
    Breast cancer-specific survival includes all events related to breast cancer and death caused by breast cancer during the follow-up period

  5. Overall Survival [ Time Frame: From date of surgery until 60 months past surgery ]
    Overall survival relates to death from any cause during the follow-up period

  6. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: From start of treatment until 28 days after termination of 24 weeks of treatment. Delayed toxicity is reported until 60 months follow-up ]
    Safety will be assessed using NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE) for reporting laboratory and non-laboratory toxicities

  7. Health-Related Quality of Life [ Time Frame: From start of study treatment until termination after 24 weeks, and then annually during the 60 months of postoperative follow-up period ]
  8. Frequency of Breast-Conserving Surgery [ Time Frame: At surgery after neoadjuvant therapy ]
    Refers to the rate of patients who are operated with breast-conserving surgery compared with mastectomy

  9. Characteristics of the Genome of Previously Untreated Tumors Before and After Exposition to Treatment [ Time Frame: Before start and during treatment, at surgery, and then annually during the 60 months of postoperative follow-up period ]
    New Generation Sequencing (NGS) is performed on biopsies from the tumors with the aim to classify the tumors according to PAM50. Repeated analyses of tumor tissue during the treatment process will be performed to identify heterogeneity and mutations which might be responsible for resistance to study treatment. Blood samples are collected to identify tumor DNA sequences which might predict recurrence during the follow-up period. Tissue and blood samples are also analyzed in case of recurrence. The results are descriptive and expressed as clustering. Units of measure are lacking

  10. Changes of the Proteome of Previously Untreated Tumors Before and After Exposition to Treatment [ Time Frame: Before start, during treatment and at surgery ]
    Proteome analyses with the intention to identify tumor-specific pathways are performed on repeated biopsies from the tumors. The results are descriptive, defined units of measure are lacking

  11. Quantification of Hormone Receptors Before and After Treatment [ Time Frame: Before start, during treatment and at surgery ]
    Immunohistochemistry on core biopsies before start, after 10 weeks of treatment, and tumor samples from the surgical specimen. Presence of estrogen receptor (ER) and progesterone receptor (PR), described as percentage in relation to the total count of tumor cells

  12. Quantification of Proliferation Beforew and After Treatment [ Time Frame: Before start, during treatment and at surgery ]
    Immunohistochemistry on core biopsies before start, after 10 weeks of treatment, and tumor samples from the surgical specimen. Presence of cells indicating proliferation by use of Ki67, described as percentage in relation to the total count of tumor cells



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent
  2. Female or male patients with breast cancer confirmed by histology
  3. Tumor and blood samples available. Luminal B type confirmed by immunohistochemistry or, preferably, genomic profiling using Next-Generation Sequencingwith ER ≥120% and Ki67 ≥20% and not HER2 amplified, or, if aged 40 or younger and/or verified lymph node metastases, luminal A type, defined as ER and PR positive ≥20% and the proliferation marker Ki 67 <20% and not HER2 amplified. Any luminal B, Luminal A with verified lymph node metastases and/or aged 40 or younger
  4. Age 18 years or older. Elderly patients in condition adequate for planned therapy
  5. Primary breast cancer >20mm in diameter and/or verified regional lymph node metastases
  6. Adequate bone marrow, renal, hepatic and cardiac functions and no other uncontrolled medical or psychiatric disorders
  7. LVEF >55%
  8. ECOG performance status 0-1
  9. Primary breast cancer as defined in p. 5 plus at most 2 morphologically characterized well-defined distant metastases accessible for stereotactic radiotherapy, provided that this treatment is available

Exclusion Criteria:

  1. Distant metastases, including node metastases in the contralateral thoracic region or in the mediastinum
  2. 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
  3. Patients in child-bearing age without adequate contraception
  4. Pregnancy or lactation
  5. Uncontrolled hypertension, heart, liver, kidney related or other medical or psychiatric disorders

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02603679


Contacts
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Contact: Mats Hellström, Coordinator +46 8 517 ext 73677 mats.hellstrom@karolinska.se
Contact: Anita Björk, Monitor +46 8 517 ext 73375 anita.bjork@karolinska.se

Locations
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Sweden
Theodoros Foukakis Recruiting
Stockholm, Sweden, 17176
Contact: Ingrid Lundin, RN    +46 8 517 ext 72310    ingrid.lundin@karolinska.se   
Sponsors and Collaborators
Thomas Hatschek
Investigators
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Study Chair: Thomas Hatschek, Assoc Prof Breast-Sarcoma Unit, Dept. of Oncology, Karolinska University Hospital
Study Director: Jonas Bergh, Professor Dept. of Oncology-Pathology, Karolinska Institutet

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Responsible Party: Thomas Hatschek, Sen. Consultant, MD, PhD, Assoc. professor, Karolinska University Hospital
ClinicalTrials.gov Identifier: NCT02603679     History of Changes
Other Study ID Numbers: PREDIX LumB
First Posted: November 13, 2015    Key Record Dates
Last Update Posted: September 8, 2016
Last Verified: September 2016

Keywords provided by Thomas Hatschek, Karolinska University Hospital:
Cyclin-Dependent Kinase Inhibitor p16

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Letrozole
Tamoxifen
Palbociclib
Anastrozole
Exemestane
Goserelin
Aromatase Inhibitors
Phenobarbital
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators