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
Condition: Breast Cancer; Hormonreceptor Positive; Her2-normal; Postneoadjuvant Treatment With CDK 4/6 Inhibitor; CPS-EG Score
MeSH terms: Breast Neoplasms
Intervention: Palbociclib PD-0332991; Placebo
Intervention description: 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; Arm B: Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a 28-day cycle for thirteen cycles
Intervention MeSH terms: Palbociclib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1250.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        Based on protocol G version 11 dated 09 April 2019

        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. In case of
             bilateral breast cancer, tumor tissue of both sides needs to be assessable.

          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 no other tissue is available, the
             residual tumor of the lymph node can be assessed. In case of bilateral breast cancer,
             hormone receptor 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. In case of bilateral breast cancer, tumor
             tissue of both sides needs to be assessable.

          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) at date of randomization.

         10. Completion of adjuvant radiotherapy according to standard guidelines (e.g. AGO Mamma,
             NCCN) is strongly recommended. If radiotherapy is not performed, the reason for this
             needs to be documented in the eCRF.

         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 is ypN+, 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.

         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 in this trial must be treated at the participating center which could be
             the Principal Investigator's 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/mm³ (< 2.0 x 109/L); Platelets <100,000/mm³ (< 100 x
             109/L); AST or ALT >1.5 x upper limit of normal (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, human immunodeficiency virus (HIV)
             or any type of hepatitis

          4. QTc >480 msec

          5. Uncontrolled electrolyte disorders (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. 10 weeks or more have passed since completion of radiotherapy at day of randomization
             and 16 weeks interval since the date of final surgery have passed.

         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

         16. Concurrent treatment with other experimental drugs. Participation in another clinical
             trial with any investigational not marketed drug within 30 days prior to
             randomization.

         17. Male patients.