Clinical trial NCT02603679: Neoadjuvant Response-guided Treatment of Luminal B-type Tumors and Luminal A-type Tumors With Node Metastases
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 type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Early-Stage Breast Carcinoma
Estrogen Receptor Positive Tumor
Keywords: Cyclin-Dependent Kinase Inhibitor p16
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
First posted: 2015-11-13
Enrollment: 181
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Radiological Objective Response Rate after Completion of the First 12-week Period of Primary Medical Treatment
timeFrame: Start of treatment until 12 weeks of treatment
Secondary outcomes:
measure: Pathological Objective Response Rate
timeFrame: From the date of surgery up to 4 weeks after surgery
measure: 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
timeFrame: From start of treatment until termination of the preoperative treatment after 24 weeks
measure: Disease-Free Survival
timeFrame: From date of surgery until 10 years past surgery
measure: Breast Cancer-Specific Survival
timeFrame: From date of surgery until 10 years past surgery
measure: Overall Survival
timeFrame: From date of surgery until 10 years past surgery
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: From start of treatment until 28 days after termination of 24 weeks of treatment. Delayed toxicity is reported until 60 months follow-up
measure: Health-Related Quality of Life
timeFrame: From start of study treatment until termination after 24 weeks, and then annually during 5 years of postoperative follow-up period
measure: Frequency of Breast-Conserving Surgery
timeFrame: At surgery after neoadjuvant therapy
measure: Characteristics of the Genome of Previously Untreated Tumors Before and After Exposition to Treatment
timeFrame: Before start and during treatment, at surgery, and then annually during the 60 months of postoperative follow-up period
measure: Changes of the Proteome of Previously Untreated Tumors Before and After Exposition to Treatment
timeFrame: Before start, during treatment and at surgery
measure: Quantification of Hormone Receptors Before and After Treatment
timeFrame: Before start, during treatment and at surgery
measure: Quantification of Proliferation Before and After Treatment
timeFrame: Before start, during treatment and at surgery
Other outcomes:
Locations:
city: Stockholm
country: Sweden
facility: Södersjukhuset
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Stockholm
country: Sweden
facility: Capio S:t Göran Hospital
Study officials:
affiliation: Breast-Sarcoma Unit, Dept. of Oncology, Karolinska University Hospital
name: Thomas Hatschek, Assoc Prof
role: STUDY_CHAIR
affiliation: Dept. of Oncology-Pathology, Karolinska Institutet
name: Jonas Bergh, Professor
role: STUDY_DIRECTOR
References: