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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

IRB GBG1115

CC 15-1373

Hospital Fairview, Florida Weston, Main Campus

Phase Phase 3

Disease Breast

Drug Palbociclib

Description

Primary Objectives

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

Secondary objectives:

• To compare between the two arms:
  • iDFS excluding second primary of non-breast cancers
  • overall survival (OS)
  • distant disease free survival (DDFS)
  • locoregional recurrences-free (LRRFS) survival
  • 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
  • health economic outcomes
  • to explore drug-drug interaction (DDI) potential for each palbociclib - endocrine combination therapy in a subset of this patient population
  • to explore correlations between exposure and efficacy and/or safety findings;

Other objectives:

• Scores and markers for their prognostic value in this specific trial setting and their predictive information on the efficacy and/or safety of palbociclib:
  • pRB immunoreactive score in residual tumor after neoadjuvant treatment
  • Cyclin D immunoreactive score in residual tumor after neoadjuvant treatment
  • residual cancer burden (RCB)6
  • clinical response to neoadjuvant chemotherapy (assessed according to chapter21.1)
  • incidence and alterations in genes, proteins, and RNAs relevant to the cell cycle (eg, CCND1 amplification, CDKN2A deletion), drug targets (eg, CDK 4/6), and tumor sensitivity and/or resistance (Ki67, pRb, tRB, cyclin E, pi3k, p16, and other markers, measured by optimal test available at the time of analysis) in tumor tissues and/or peripheral blood.
  • Low and high risk groups (defined by Endopredict®, ROR or other any other available test at the time of analysis)
  • low and high risk groups defined by a standardized image analysis system for Ki67
  • circulating tumor cells (CTCs) and DNA (ctDNA)

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/mm³ (< 2.0 x 10⁹/L); Platelets <100,000/mm³ (< 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 (see appendix 21.3)or drugs that are known to prolong the QT interval (see appendix 21.4).
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.