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

NCT ID: NCT02296801

Last Updated: 2022-01-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 307 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2019-03-31

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).

Conditions

Breast Cancer; Breast Carcinoma; Breast Tumors

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

A: letrozole

letrozole 2.5 mg tablet orally daily for 14 weeks

Group Type: ACTIVE_COMPARATOR

Letrozole

Intervention Type: DRUG

B: letrozole then letrozole + palbociclib

letrozole 2.5 mg orally daily plus beginning 2 weeks after starting letrozole, palbociclib 125 mg capsule orally daily for 1 week then 1 week off, then a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of letrozole therapy

Group Type: EXPERIMENTAL

Letrozole

Intervention Type: DRUG

palbociclib

Intervention Type: DRUG

C: palbociclib then letrozole + palbociclib

palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy

Group Type: EXPERIMENTAL

Letrozole

Intervention Type: DRUG

palbociclib

Intervention Type: DRUG

D: letrozole + palbociclib

letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy

Group Type: EXPERIMENTAL

Letrozole

Intervention Type: DRUG

palbociclib

Intervention Type: DRUG

Combined Groups B+D+C

Combined data

Group Type: OTHER

Letrozole

Intervention Type: DRUG

palbociclib

Intervention Type: DRUG

Interventions

Letrozole

Intervention Type: DRUG

palbociclib

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

Royal Marsden NHS Foundation Trust

OTHER

Sponsor Role: collaborator

Institute of Cancer Research, United Kingdom

OTHER

Sponsor Role: collaborator

NSABP Foundation Inc

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Norman Wolmark, MD

Role: PRINCIPAL_INVESTIGATOR

NSABP Foundation Inc

Locations

Long Beach Memorial Medical Center-Todd Cancer Institute

Long Beach, California, United States

University of Miami Hospital and Clinics - Sylvester Comprehensive Cancer Center

Miami, Florida, United States

Cancer Care Specialists of Central Illinois

Decatur, Illinois, United States

Norton Healthcare Pavillion

Louisville, Kentucky, United States

Norton Cancer Institute - Suburban, Norton Medical Plaza II

Louisville, Kentucky, United States

Norton Cancer Institute - Brownsboro Medical Plaza I

Louisville, Kentucky, United States

Metro-Minnesota CCOP

Saint Louis Park, Minnesota, United States

Hope Women's Cancer Centers

Asheville, North Carolina, United States

Providence Oncology and Hematology Clinic

Portland, Oregon, United States

Pinnacle Health Ortenzio Cancer Center

Mechanicsburg, Pennsylvania, United States

Allegheny General Hospital

Pittsburgh, Pennsylvania, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Women and Infants Hospital of Rhode Island

Providence, Rhode Island, United States

Baylor College of Medicine

Houston, Texas, United States

Joe Arrington Cancer Research and Treatment Center

Lubbock, Texas, United States

Sentara Martha Jefferson Hospital-Phillips Family Cancer Center

Charlottesville, Virginia, United States

Virginia Commonwealth University

Richmond, Virginia, United States

Swedish Cancer Institute

Seattle, Washington, United States

West Virginia University

Morgantown, West Virginia, United States

Centre Hospitalier de l'Universite de Montreal

Montreal, Quebec, Canada

Jewish General Hospital

Montreal, Quebec, Canada

McGill University Health Center

Montreal, Quebec, Canada

CHU de Quebec - Universite Laval

Québec, Quebec, Canada

Milton Keynes Hospital

Milton Keynes, Buckinghamshire, United Kingdom

Hinchingbrooke Hospital

Huntingdon, Cambridgeshire, United Kingdom

Royal Cornwall Hospital, Treliske

Truro, Cornwall, United Kingdom

Royal Devon and Exeter Hospital

Exeter, Devon, United Kingdom

Royal Sussex County Hospital

Brighton, East Sussex, United Kingdom

Southend Hospital

Westcliff-on-Sea, Essex, United Kingdom

Darent Valley Hospital

Dartford, Kent, United Kingdom

Maidstone Hospital

Maidstone, Kent, United Kingdom

Royal Liverpool University Hospital

Liverpool, Merseyside, United Kingdom

James Paget University Hospital

Great Yarmouth, Norfolk, United Kingdom

Musgrove Park Hospital

Taunton, Somerset, United Kingdom

Weston General Hospital

Weston-super-Mare, Somerset, United Kingdom

The Royal Marsden Hospital

Sutton, Surrey, United Kingdom

Salisbury Hospital

Salisbury, Wiltshire, United Kingdom

Kidderminster Hospital

Kidderminster, Worcestershire, United Kingdom

Alexandra Hospital

Redditch, Worcestershire, United Kingdom

Worcestershire Royal Hospital

Worcester, Worcestershire, United Kingdom

Belfast City Hospital

Belfast, , United Kingdom

Royal Bournemouth Hospital

Bournemouth, , United Kingdom

Western General Hospital (Edinburgh Cancer Centre)

Edinburgh, , United Kingdom

St James' University Hospital

Leeds, , United Kingdom

Barnet Hospital

London, , United Kingdom

Whittington Hospital

London, , United Kingdom

University College London Hospitals

London, , United Kingdom

The Royal Marsden Hospital

London, , United Kingdom

Charing Cross Hospital

London, , United Kingdom

Nottingham University Hospitals NHS Trust, City Campus

Nottingham, , United Kingdom

Derriford Hospital

Plymouth, , United Kingdom

Singleton Hospital

Swansea, , United Kingdom

Countries

United States; Canada; United Kingdom

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

WI180455

Identifier Type: OTHER

Identifier Source: secondary_id

NSABP FB-11

Identifier Type: -

Identifier Source: org_study_id