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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:

Unknown status

Phase:

Phase 2

Trial Eligibility

Document

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

  • ORG STUDY ID: NSABP FB-11
  • SECONDARY ID: WI180455
  • NCT ID: NCT02296801

Conditions

  • Breast Cancer
  • Breast Carcinoma
  • Breast Tumors

Interventions

DrugSynonymsArms
LetrozoleA: letrozole
palbociclibB: letrozole then letrozole + palbociclib

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

NameTypeDescriptionInterventions
A: letrozoleActive Comparatorletrozole 2.5 mg tablet orally daily for 14 weeks
  • Letrozole
B: letrozole then letrozole + palbociclibExperimentalletrozole 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 + palbociclibExperimentalpalbociclib 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 + palbociclibExperimentalletrozole 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Measurement of the proliferation marker Ki67 (% positive tumor cells)
Time Frame:Baseline and at 14 weeks
Safety Issue:
Description:The change in Ki67 from baseline to 14 weeks.

Secondary Outcome Measures

Measure:Pathological Complete Response (pCR): Number of patients with no lesions in breast and nodes at time of surgery
Time Frame:14 weeks
Safety Issue:
Description:
Measure:Preoperative Endocrine Prognostic Index (PEPI) score:
Time Frame:14 weeks
Safety Issue:
Description:The PEPI score estimates the risk of cancer recurrence after treatment.
Measure:Number and severity of adverse events
Time Frame:baseline and weekly through 12 months after randomization
Safety Issue:
Description:
Measure:Molecular and genetic profiles of samples collected.
Time Frame:Baseline, week 2 and week 14
Safety Issue:
Description:
Measure:Measurement of Ki67 marker
Time Frame:Week 2 and week 14
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Unknown status
Lead Sponsor:NSABP Foundation Inc

Last Updated

August 14, 2018