Clinical trial NCT02296801: A Phase II Randomized Study Evaluating the Biological and Clinical Effects of the Combination of Palbociclib With Letrozole as Neoadjuvant Therapy in Post-Menopausal Women With Estrogen-Receptor Positive Primary Breast Cancer
Official title: A Phase II Randomized Study Evaluating the Biological and Clinical Effects of the Combination of Palbociclib With Letrozole as Neoadjuvant Therapy in Post-Menopausal Women With Estrogen-Receptor Positive Primary Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Breast Carcinoma
Breast Tumors
Lead sponsor: NSABP Foundation Inc
Sponsor class: NETWORK
Collaborators: name: Pfizer
name: Royal Marsden NHS Foundation Trust
name: Institute of Cancer Research, United Kingdom
First posted: 2014-11-20
Enrollment: 307
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will look at effects the combination of palbociclib and letrozole may have on estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer tumors which have not yet been treated. Letrozole is a type of endocrine therapy called an aromatase inhibitor (AI) and is standard treatment for post-menopausal women with ER-positive/HER2-negative breast cancer.

Detailed description: The FB-11 study is a Phase II, randomized, open label, four arm study to examine the biological and clinical effect of neoadjuvant letrozole with or without palbociclib in the first-line treatment of estrogen-receptor (ER) positive, HER2-negative early invasive breast cancer. The co-primary aims of this study are to to compare the changes in the proliferation marker Ki67, and to compare clinical response after 14 weeks of therapy with letrozole with or without palbociclib.

The FB-11 study initiative is a joint partnership between the NSABP Foundation, Inc. (NSABP) Department of Site and Study Management (DSSM) and United Kingdom (UK) co-investigators at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research (ICR). Parallel protocols will be conducted in the US and Canada (FB-11), and the UK (PALLET) with joint analysis of interim and final data.

Postmenopausal women, newly diagnosed with ER-positive/HER2-negative early breast cancer, who are suitable candidates for neoadjuvant endocrine therapy will be invited to join the FB-11/PALLET trial. Approximately 306 patients will be accrued to this study. Each collaborative group will recruit at least 1/3 and no more than 2/3 of the target accrual.

Patients will be randomized to one of four treatment arms (3:2:2:2 ratio). Treatment in the first 14 weeks of neoadjuvant therapy will be:Arm A Letrozole alone; Arm B Letrozole for 2 weeks followed by letrozole + palbociclib to week 14; Arm C Palbociclib for 2 weeks followed by letrozole + palbociclib to week 14; Arm D Letrozole + palbociclib to week 14.

Letrozole will be administered orally as a 2.5mg daily tablet. Palbociclib will be administered orally as 125mg capsules, daily on a schedule of 3 weeks (21 days) on, 1 week (7 days) off of a 4 week \[28 day\] cycle.

The end of study therapy for patients in Arm A will be completion of week 14. Patients in Arms B, C, and D will complete study therapy following 14 days of palbociclib in the final treatment cycle past 14 weeks if treatment delays have occurred.

Note: After week 14 (end of study therapy) all patients should continue letrozole until surgery. Letrozole is not considered study therapy beyond completion of week 14 for Arm A or after 14 days of palbociclib in the final treatment cycle for patients in Arms B, C, and D.

Following completion of study therapy, surgery will be scheduled for 15-18 weeks post-randomization. Post-surgical treatment will be at discretion of treating clinician, following local protocols, and not influenced by allocation of treatment within the FB-11/PALLET study.

Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).

Eligibility criteria: Inclusion Criteria:

* Patients must be postmenopausal women defined as: Age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or Age 55 or younger with no menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or Age greater than or equal to 18 with documented bilateral oophorectomy.
* Operable ER-positive/HER2- negative, invasive early breast cancer, suitable for neoadjuvant AI treatment. HER2-negative as determined by American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) guidelines.
* No known severe hypersensitivity reactions to compounds similar to palbociclib or palbociclib excipients or to endocrine treatments.
* A breast tumor with an ultrasound size of at least 2.0 cm.
* Patients must have the ability to swallow oral medication.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* At the time of randomization, blood counts performed within 4 weeks prior to randomization must meet the following criteria: absolute neutrophil count (ANC) must be greater than or equal to 1500/mm3; Platelet count must be greater than or equal to 100,000/mm3; Hemoglobin must be greater than or equal to 10 g/dL.
* international normalized ratio (INR) must be within normal limits of the local laboratory ranges.
* The following criteria for evidence of adequate hepatic function performed within 4 weeks prior to study entry must be met: total bilirubin must be less than or equal to upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation greater than ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and alkaline phosphatase must be must be less than or equal to 1.5 x ULN for the lab; and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be less than or equal to 1.5 x ULN for the lab.
* Serum creatinine performed within 4 weeks prior to study entry must be less than or equal to 1.25 x ULN or estimated creatinine clearance less than 60 mL/min (as calculated using the method standard for the institutions).

Exclusion Criteria:

* Active hepatitis B or hepatitis C with abnormal liver function tests.
* HIV positive patients receiving antivirals.
* Premenopausal or peri-menopausal women.
* Inflammatory/inoperable breast cancer.
* HER2-positive as determined using ASCO-CAP Guidelines.
* Concurrent use (defined as use within 4 weeks prior to baseline tissue sample being taken) of hormone replacement therapy (HRT) or any other estrogen-containing medication (including vaginal estrogens)
* Prior endocrine therapy for breast cancer.
* Any invasive malignancy within previous 5 years (other than basal cell carcinoma or cervical carcinoma in situ).
* Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow up such as: Active infection or chronic infection requiring chronic suppressive antibiotics; Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function; Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids); Seizure disorders requiring medication.
* Diagnosis by fine needle aspiration (FNA) alone or excisional biopsy or lumpectomy performed prior to study entry.
* Surgical axillary staging procedure prior to study procedure (with exception of FNA or core biopsy).
* Definitive clinical or radiologic evidence of metastatic disease.
* History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral ductal carcinoma in situ (DCIS) treated with radiotherapy or contralateral invasive breast cancer at any time.
* Any treatment, including radiotherapy, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to study entry.
* Use of any medication or substances that are strong inhibitors or inducers of CYP3A isoenzymes.
* Class III or Class IV myocardial disease as described by the New York Heart Association; a recent history (within 6 months) of myocardial infarction, or symptomatic arrhythmia at the time of randomization. Class III: Patients with cardiac disease resulting in marked limitation of physical activity. Such patients are comfortable at rest. Less than ordinary physical activity that causes fatigue, palpitation, dyspnea, or anginal pain. Class IV: Patients with cardiac disease resulting in inability to perform any physical activity without discomfort. Symptoms of cardiac insufficiency or anginal syndrome may be present even at rest.
* QTc greater than 480 msec or a family or personal history of long or short QT syndrome, Brugada syndrome or know history of QTc prolongation, or Torsade de Pointes (TdP).
* The investigator should assess the patient to determine if she has any psychiatric or addictive disorder or other condition that, in the opinion of the investigator, would preclude her from meeting the study requirements.

Primary outcomes:
measure: Measurement of the Proliferation Marker Ki67 (% Positive Tumor Cells)
timeFrame: Baseline and at 14 weeks
measure: Clinical Response : Number of Patients Who Have Resolution of Measurable Lesions or no New Lesions or Other Signs of Disease Progression Compared to Baseline.
timeFrame: Baseline and at 14 weeks
Secondary outcomes:
measure: Pathological Complete Response (pCR): Number of Patients With no Lesions in Breast and Nodes at Time of Surgery
timeFrame: 14 weeks
measure: Preoperative Endocrine Prognostic Index (PEPI) Score:
timeFrame: 14 weeks
measure: Number and Severity of Adverse Events
timeFrame: Baseline and weekly through 12 months after randomization
measure: Measurement of Ki67 Marker
timeFrame: Week 2 and week 14
measure: Comparison of Surgical Intent (Mastectomy; Breast Conservation)
timeFrame: Time frame between baseline and surgery date. (Note-surgical intent happened before randomization).
Other outcomes:
Locations:
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center-Todd Cancer Institute
state: California
city: Miami
country: United States
facility: University of Miami Hospital and Clinics - Sylvester Comprehensive Cancer Center
state: Florida
city: Decatur
country: United States
facility: Cancer Care Specialists of Central Illinois
state: Illinois
city: Louisville
country: United States
facility: Norton Healthcare Pavillion
state: Kentucky
city: Louisville
country: United States
facility: Norton Cancer Institute - Suburban, Norton Medical Plaza II
state: Kentucky
city: Louisville
country: United States
facility: Norton Cancer Institute - Brownsboro Medical Plaza I
state: Kentucky
city: Saint Louis Park
country: United States
facility: Metro-Minnesota CCOP
state: Minnesota
city: Asheville
country: United States
facility: Hope Women's Cancer Centers
state: North Carolina
city: Portland
country: United States
facility: Providence Oncology and Hematology Clinic
state: Oregon
city: Mechanicsburg
country: United States
facility: Pinnacle Health Ortenzio Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Women and Infants Hospital of Rhode Island
state: Rhode Island
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research and Treatment Center
state: Texas
city: Charlottesville
country: United States
facility: Sentara Martha Jefferson Hospital-Phillips Family Cancer Center
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Montreal
country: Canada
facility: Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Quebec City
country: Canada
facility: CHU de Quebec - Universite Laval
state: Quebec
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes Hospital
state: Buckinghamshire
city: Huntingdon
country: United Kingdom
facility: Hinchingbrooke Hospital
state: Cambridgeshire
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital, Treliske
state: Cornwall
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: Devon
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
state: East Sussex
city: Westcliff-on-Sea
country: United Kingdom
facility: Southend Hospital
state: Essex
city: Dartford
country: United Kingdom
facility: Darent Valley Hospital
state: Kent
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
state: Kent
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: Merseyside
city: Great Yarmouth
country: United Kingdom
facility: James Paget University Hospital
state: Norfolk
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
state: Somerset
city: Weston-Super-Mare
country: United Kingdom
facility: Weston General Hospital
state: Somerset
city: Sutton
country: United Kingdom
facility: The Royal Marsden Hospital
state: Surrey
city: Salisbury
country: United Kingdom
facility: Salisbury Hospital
state: Wiltshire
city: Kidderminster
country: United Kingdom
facility: Kidderminster Hospital
state: Worcestershire
city: Redditch
country: United Kingdom
facility: Alexandra Hospital
state: Worcestershire
city: Worcester
country: United Kingdom
facility: Worcestershire Royal Hospital
state: Worcestershire
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital (Edinburgh Cancer Centre)
city: Leeds
country: United Kingdom
facility: St James' University Hospital
city: London
country: United Kingdom
facility: Barnet Hospital
city: London
country: United Kingdom
facility: Whittington Hospital
city: London
country: United Kingdom
facility: University College London Hospitals
city: London
country: United Kingdom
facility: The Royal Marsden Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust, City Campus
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Swansea
country: United Kingdom
facility: Singleton Hospital
Study officials:
affiliation: NSABP Foundation Inc
name: Norman Wolmark, MD
role: PRINCIPAL_INVESTIGATOR
References: