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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

NCT02296801

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

A Phase II Randomized Study Evaluating the Biological and Clinical Effects of the Combination of <span class="go-doc-concept go-doc-intervention">Palbociclib</span> With Letrozole as Neoadjuvant Therapy in Post-Menopausal Women With Estrogen-Receptor Positive Primary <span class="go-doc-concept go-doc-disease">Breast Cancer</span>

Title

  • Brief 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
  • 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
  • Clinical Trial IDs

    NCT ID: NCT02296801

    ORG ID: NSABP FB-11

    NCI ID: WI180455

    Trial Conditions

    Breast Cancer

    Breast Carcinoma

    Breast Tumors

    Trial Interventions

    Drug Synonyms Arms
    Letrozole A: letrozole, B: letrozole then letrozole + palbociclib, C: palbociclib then letrozole + palbociclib, D: letrozole + palbociclib
    palbociclib B: letrozole then letrozole + palbociclib, C: palbociclib then letrozole + palbociclib, D: letrozole + palbociclib

    Trial Purpose

    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).

    Trial Arms

    Name Type Description Interventions
    A: letrozole Active Comparator letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole
    B: letrozole then letrozole + palbociclib Experimental 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 Letrozole, palbociclib
    C: palbociclib then letrozole + palbociclib Experimental 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 Letrozole, palbociclib
    D: letrozole + palbociclib Experimental 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 Letrozole, palbociclib

    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

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Measurement of the proliferation marker Ki67 (% positive tumor cells)

    Clinical Complete Response (cCR): Number of patients who have resolution of measurable lesions or no new lesions or other signs of disease progression compared to baseline.

    Secondary Outcome Measures

    Pathological Complete Response (pCR): Number of patients with no lesions in breast and nodes at time of surgery

    Preoperative Endocrine Prognostic Index (PEPI) score:

    Number and severity of adverse events

    Molecular and genetic profiles of samples collected.

    Measurement of Ki67 marker

    Trial Keywords