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A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery

NCT01864746

Description:

The PENELOPEB study is designed to demonstrate that in the background of standard anti-hormonal therapy palbociclib provides superior invasive disease-free survival (iDFS) compared to placebo in pre- and postmenopausal women with HR-positive/HER2-normal early breast cancer at high risk of relapse after showing less than pathological complete response to neoadjuvant taxane- containing chemotherapy. Considering the high risk of recurrence in patients after neoadjuvant chemotherapy and a high CPS-EG score, palbociclib appears to be an attractive option with a favourable safety profile for these patients.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

A Study of <span class="go-doc-concept go-doc-intervention">Palbociclib</span> in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After <span class="go-doc-concept go-doc-intervention">Neoadjuvant Chemotherapy</span> and Surgery

Title

  • Brief Title: A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery
  • Official Title: Phase III Study Evaluating Palbociclib (PD-0332991), a Cyclin-Dependent Kinase (CDK) 4/6 Inhibitor in Patients With Hormone-receptor-positive, HER2-normal Primary Breast Cancer With High Relapse Risk After Neoadjuvant Chemotherapy "PENELOPEB"
  • Clinical Trial IDs

    NCT ID: NCT01864746

    ORG ID: GBG78/BIG 1-13/NSABP-B-54-I

    NCI ID: 2013-001040-62

    Trial Conditions

    Breast Cancer

    Hormonreceptor Positive

    Her2-normal

    Postneoadjuvant Treatment With CDK 4/6 Inhibitor

    CPS-EG Score

    Trial Interventions

    Drug Synonyms Arms
    Palbociclib PD-0332991 Ibrance Palbociclib
    Placebo Placebo

    Trial Purpose

    The PENELOPEB study is designed to demonstrate that in the background of standard
    anti-hormonal therapy palbociclib provides superior invasive disease-free survival (iDFS)
    compared to placebo in pre- and postmenopausal women with HR-positive/HER2-normal early
    breast cancer at high risk of relapse after showing less than pathological complete response
    to neoadjuvant taxane- containing chemotherapy. Considering the high risk of recurrence in
    patients after neoadjuvant chemotherapy and a high CPS-EG score, palbociclib appears to be
    an attractive option with a favourable safety profile for these patients.

    Detailed Description

    About one third of patients with hormone-receptor (HR)-positive, HER2- normal breast cancer
    and residual disease after neoadjuvant chemotherapy have a substantial risk of relapse. The
    clinical-pathologic stage - estrogen/grade (CPS-EG)1 combining clinical stage before
    neoadjuvant treatment, pathological stage after neoadjuvant treatment, grading and
    estrogen-receptor status can be used to identify these high-risk patients. The CPS-EG score
    was additionally validated in 2454 patients with HRpositive/ HER2-normal tumors from the
    German neoadjuvant studies' metadatabase. Patients who had a score of 3 or higher or Score 2
    and ypN+ disease show a 3-years iDFS of 77% despite adequate local therapy and adjuvant
    endocrine treatment. Cyclin dependent kinases (CDK), a group of serine/threonine kinases,
    play a key role in regulating cell cycle progression by interacting with specific cyclin
    proteins in luminal-type tumors.2,3 PD-0332991 (palbociclib) is an oral, highly selective
    inhibitor of CDK4/6 kinase activity that prevents cellular DNA synthesis by prohibiting
    progression of the cell cycle from G1 to S phase through blocking retinoblastoma (Rb)
    phosphorylation.4 Preclinical studies identified luminal ER subtype, elevated expression of
    cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to
    palbociclib.

    Trial Arms

    Name Type Description Interventions
    Palbociclib Experimental Palbociclib at a dose of 125 mg once daily, day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles Palbociclib PD-0332991
    Placebo Placebo Comparator Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles Placebo

    Eligibility Criteria

    Inclusion Criteria

    1. Written informed consent prior to beginning specific protocol procedures, including
    expected cooperation of the patients for the treatment and follow-up, must be
    obtained and documented according to the local regulatory requirements.

    2. Willingness and ability to provide archived formalin fixed paraffin embedded tissue
    block or a partial block from surgery after neoadjuvant chemotherapy and from
    core-biopsy before start of neoadjuvant chemotherapy, which will be used for
    centralized retrospective confirmation of hormone- and HER2-status and to evaluate
    correlation between genes, proteins, and mRNAs relevant to the endocrine and cell
    cycle pathways and sensitivity/resistance to the investigational agents.

    3. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the
    breast.

    4. Residual invasive disease post-neoadjuvant either in the breast or as residual nodal
    invasion.

    5. Centrally confirmed hormone-receptor-positive (>=1% ER and/or PR positive stained
    cells) and HER2-normal (IHC score 0-1 or FISH negative (in-situ hybridization (ISH)
    ratio) <2.0 status) assessed preferably on tissue from post-neoadjuvant residual
    invasive disease or core biopsy of the breast, or if not possible, of residual nodal
    invasion.

    In case of bilateral breast cancer hormonreceptor positivity and HER2-normal status
    has to be centrally confirmed for both sides.

    6. Centrally assessed Ki-67, pRB, and Cyclin D1 status assessed preferably on
    post-neoadjuvant residual invasive disease of the breast, or if not possible, of
    residual nodal invasion or core biopsy.

    7. Patients must have received neoadjuvant chemotherapy of at least 16 weeks. This
    period must include 6 weeks of a taxane -containing neoadjuvant therapy (Exception:
    For patients with progressive disease that occurred after at least 6 weeks of
    taxane-containing neoadjuvant treatment, a total treatment period of less than 16
    weeks is also eligible).

    8. Adequate surgical treatment including resection of all clinically evident disease and
    ipsilateral axillary lymph node dissection. Histologically complete resection (R0) of
    the invasive and ductal in situ tumor is required in case of breast conserving
    surgery as the final treatment. No evidence of gross residual disease (R2) is
    required after total mastectomy (R1 resection is acceptable). Axillary dissection is
    not required in patients with a negative sentinel-node biopsy before (pN0, pN+(mic))
    or after (ypN0, ypN+(mic) neoadjuvant chemotherapy.

    9. Less than 16 weeks interval since the date of final surgery or less than 10 weeks
    from completing radiotherapy (whichever occurs last) and date of randomization.

    10. Completion of adjuvant radiotherapy. Radiotherapy is indicated to the breast in all
    patients treated with breast conserving surgery and to chest wall in all patients
    with cT3/cT4, R1 or ypN+ disease treated by mastectomy.

    11. No clinical evidence for locoregional or distant relapse during or after preoperative
    chemotherapy. Local progression during chemotherapy is not an exclusion criterion.

    12. A clinical-pathologic stage - estrogen/grade (CPS-EG) score of >=3, or score 2 if
    nodal status at surgery isypN+, calculated using local estrogen receptor status and
    grade assessed on either core biopsies taken before start of neoadjuvant treatment or
    surgical specimen (see chapter 21.1).

    13. Age at diagnosis at least 18 years.

    14. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (see
    Appendix 21.2).

    15. Resolution of all acute toxic effects of prior anti cancer therapy or surgical
    procedures to NCI CTCAE version 4.0 Grade 1 (except alopecia or other toxicities not
    considered a safety risk for the patient at investigator's discretion).

    16. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast
    cancer.

    17. The patient must be accessible for scheduled visits, treatment and follow-up.
    Patients registered on this trial must be treated at the participating center which
    could be the Principal or a Co- investigator's site.

    Exclusion Criteria

    1. Known severe hypersensitivity reactions to compounds similar to palbociclib or
    palbociclib/placebo excipients or to endocrine treatments.

    2. Inadequate organ function immediate prior to randomization including: Hemoglobin
    <10g/dL (100g/L) ANC < 2000/mm (< 2.0 x 109/L); Platelets <100,000/mm (< 100 x
    109/L); AST and/or ALT >1.5 x upper normal limits (ULN); alkaline phosphatase > 2.5 x
    ULN, total serum bilirubin > 1.25 x ULN; serum creatinine >1.25 x ULN or estimated
    creatinine clearance < 60 mL/min as calculated using the method standard for the
    institution; severe and relevant co-morbidity that would interact with the
    participation in the study

    3. Evidence for infection including wound infections, HIV, Hepatitis

    4. QTc >480 msec or a family or personal history of long or short QT syndrome, Brugada
    syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).

    5. Uncontrolled electrolyte disorders that can compound the effects of a QTc prolonging
    drug (eg, hypocalcemia, hypokalemia, hypomagnesemia).

    6. Any of the following within 6 months of randomization: myocardial infarction,
    severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade
    2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft,
    symptomatic congestive heart failure, cerebrovascular accident including transient
    ischemic attack, or symptomatic pulmonary embolism.

    7. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any
    upper gastrointestinal surgery including gastric resection.

    8. Prior malignancy (including invasive or ductal in-situ breast cancer) within 5 years
    prior to randomization, except curatively treated basal cell carcinoma of the skin
    and carcinoma in situ of the cervix.

    9. Current severe acute or uncontrolled chronic systemic disease (e.g. diabetes
    mellitus) or psychiatric condition or laboratory abnormality that may increase the
    risk associated with study participation or investigational product administration or
    may interfere with the interpretation of study results and, in the judgment of the
    investigator, would make the patient inappropriate for entry into this study.

    10. Recent (within the past year) or active suicidal behavior.

    11. Pregnancy or lactation period. Women of childbearing potential must implement
    adequate non-hormonal contraceptive measures (barrier methods, intrauterine
    contraceptive devices, sterilization) during study treatment and for 90 days after
    discontinuation. A serum pregnancy test must be negative in premenopausal women or
    women with amenorrhea of less than 12 months.

    12. Major surgery within 2 weeks prior to randomization.

    13. Prior endocrine treatment in addition to neoadjuvant chemotherapy is acceptable.
    Adjuvant endocrine treatment can be started anytime post-surgery.

    14. Prior treatment with any CDK4/6 inhibitor.

    15. Patients treated within the last 7 days prior to randomization and/or concurrent use
    of drugs known to be strong CYP3A4 inhibitors or inducers or drugs that are known to
    prolong the QT interval

    16. Concurrent treatment with other experimental drugs. Participation in another clinical
    trial with any investigational not marketed drug within 30 days prior to study entry.

    17. Male patients.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Invasive disease free survival (iDFS) for palbociclib vs. placebo in patients with high CPS-EG score after neoadjuvant chemotherapy receiving standard adjuvant endocrine therapy for HR-positive/HER2-normal primary breast cancer.

    Secondary Outcome Measures

    iDFS excluding second non-breast cancers

    distant disease free survival (DDFS)

    overall survival (OS)

    iDFS per treatment group in patients with luminal-B tumors (as determined by e.g. PAM50 or any other commercially available test at the time of analysis)

    compliance and safety according to NCI-CTCAE Version 4.0

    patients reported outcomes EORTC QLQ C30, EORTC QLQ BR-23, EORTC QLQ FA-13 Fatigue, GAD7 patient self-rating mood scale

    quality-adjusted life years (QALY), health economic outcomes EQ-5D

    Area under the Curve (AUC), Cmax

    correlations between exposure and efficacy and/or safety findings

    Trial Keywords