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 | Completed Phase 3 Results DMC

• 2 other identifiers: GBG78/BIG 1-13/NSABP-B-54-I2013-001040-62
• Study Type: interventional
• Target: 1,250
• Locations: 10 countries
• Sites: 10

Brief 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.

Conditions

Breast Cancer; Hormonreceptor Positive; Her2-normal; Postneoadjuvant Treatment With CDK 4/6 Inhibitor; CPS-EG Score

Outcome Measures

Primary Outcomes (1)

• 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.

  Invasive disease-free survival (iDFS) is defined according to Hudis (J Clin Oncol 2007) as the time period between randomization and first event (ipsi- or contralateral invasive in-breast or loco-regional recurrence, distant recurrence, death from breast cancer, death from non-breast cancer cause, death from unknown cause, invasive contralateral breast cancer, second primary invasive cancer (non-breast)) assessed until the end of study.

  From date of randomisation to data cut off: 24 August 2020 (approximately 6 years and 6 months)

Secondary Outcomes (3)

• iDFS Excluding Second Non-breast Cancers

  From date of randomisation to data cut off: 24 August 2020 (approximately 6 years and 6 months)

• Distant Disease Free Survival (DDFS)

  From date of randomisation to data cut off: 24 August 2020 (approximately 6 years and 6 months)

• Overall Survival (OS)

  From date of randomisation to data cut off: 24 August 2020 (approximately 6 years and 6 months)

Study Arms (2)

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

Drug: 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

Drug: Placebo

Interventions

Palbociclib PD-0332991 DRUG

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

Also known as: Ibrance

Palbociclib

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• Histologically confirmed unilateral or bilateral primary invasive carcinoma of the breast.
• Residual invasive disease post-neoadjuvant either in the breast or as residual nodal invasion.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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).
• Age at diagnosis at least 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• 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).
• Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast cancer.

You may not qualify if:

• Known severe hypersensitivity reactions to compounds similar to palbociclib or palbociclib/placebo excipients or to endocrine treatments.
• 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
• Evidence for infection including wound infections, human immunodeficiency virus (HIV) or any type of hepatitis
• QTc \>480 msec
• Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypomagnesemia).
• 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.
• Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.
• 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.
• 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.
• Recent (within the past year) or active suicidal behavior.
• 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.
• Major surgery within 2 weeks prior to randomization.
• 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.
• Prior treatment with any CDK4/6 inhibitor.
• Patients treated within the last 7 days prior to randomization and/or concurrent use of drugs known to be strong CYP3A4 inhibitors or inducers

Sponsors & Collaborators

• GBG Forschungs GmbH: lead
• Pfizer: collaborator
• AGO Study Group: collaborator
• NSABP Foundation Inc: collaborator
• Breast International Group: collaborator

Study Sites (11)

NSABP Foundation

Pittsburgh, Pennsylvania, 15212, United States

Location

Contact: Australia and New Zealand Breast Cancer Trials Group

Newcastle, NSW 2310, PO Box 155, Australia

Location

Contact: Austrian Breast & Colorectal Cancer Study Group

Vienna, 1090, Austria

Location

Contact: NSABP Foundation

Multiple Locations, Canada

Location

Contact: UNICANCER

Paris, 75654, France

Location

Contact: German Breast Group

Neu-Isenburg, 63263, Germany

Location

Contact: Cancer Trials Ireland

Dublin, 2, Ireland

Location

Contact: Japan Breast Cancer Research Group

Tokyo, 103-0016, Japan

Location

Contact: Korea Cancer Study Group

Seoul, 138-736, South Korea

Location

GEICAM

San Sebastián de los Reyes, 28703, Spain

Location

Contact: Institute of Cancer Research

London, SW7 3RP, United Kingdom

Location

Related Publications (9)

• Mittendorf EA, Jeruss JS, Tucker SL, Kolli A, Newman LA, Gonzalez-Angulo AM, Buchholz TA, Sahin AA, Cormier JN, Buzdar AU, Hortobagyi GN, Hunt KK. Validation of a novel staging system for disease-specific survival in patients with breast cancer treated with neoadjuvant chemotherapy. J Clin Oncol. 2011 May 20;29(15):1956-62. doi: 10.1200/JCO.2010.31.8469. Epub 2011 Apr 11.

  PMID: 21482989 BACKGROUND

• Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011 Jul 7;11(8):558-72. doi: 10.1038/nrc3090.

  PMID: 21734724 BACKGROUND

• ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 Sep 6;489(7414):57-74. doi: 10.1038/nature11247.

  PMID: 22955616 BACKGROUND

• Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi: 10.1186/bcr2419.

  PMID: 19874578 BACKGROUND

• Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-22. doi: 10.1200/JCO.2007.10.6823. Epub 2007 Sep 4.

  PMID: 17785706 BACKGROUND

• Mauri D, Pavlidis N, Ioannidis JP. Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis. J Natl Cancer Inst. 2005 Feb 2;97(3):188-94. doi: 10.1093/jnci/dji021.

  PMID: 15687361 BACKGROUND

• von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C, Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 2012 May 20;30(15):1796-804. doi: 10.1200/JCO.2011.38.8595. Epub 2012 Apr 16.

  PMID: 22508812 BACKGROUND

• Loibl S, Marme F, Martin M, Untch M, Bonnefoi H, Kim SB, Bear H, McCarthy N, Mele Olive M, Gelmon K, Garcia-Saenz J, Kelly CM, Reimer T, Toi M, Rugo HS, Denkert C, Gnant M, Makris A, Koehler M, Huang-Bartelett C, Lechuga Frean MJ, Colleoni M, Werutsky G, Seiler S, Burchardi N, Nekljudova V, von Minckwitz G. Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial. J Clin Oncol. 2021 May 10;39(14):1518-1530. doi: 10.1200/JCO.20.03639. Epub 2021 Apr 1.

  PMID: 33793299 RESULT

• Hahnen E, Hauke J, Gelmon K, Marme F, Ernst C, Martin M, Untch M, Bonnefoi H, Knudsen E, Im SA, DeMichele A, Van't Veer L, Kim SB, Bear H, McCarthy N, Rhiem K, Turner N, Witkiewicz A, Rojo F, Filipits M, Martin LA, Fasching PA, Schem C, Becker K, Garcia-Saenz JA, Kelly CM, Reimer T, Toi M, Rugo HS, Denkert C, Gnant M, Makris A, Liu Y, Valota O, Felder B, Weber K, Nekljudova V, Loibl S. BRCA1/2 and Other Predisposition Genes in High-Risk Hormone Receptor+/Human Epidermal Growth Factor Receptor 2- Breast Cancer Treated With Endocrine Therapy With or Without Palbociclib: A Secondary PENELOPE-B Study Analysis. JCO Precis Oncol. 2025 Apr;9:e2400742. doi: 10.1200/PO-24-00742. Epub 2025 Apr 10.

  PMID: 40209141 DERIVED

Related Links

• General trial information

MeSH Terms

Conditions

Breast Neoplasms

Interventions

palbociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Prof. Dr. Sibylle Loibl
• Organization: German Breast Group (GBG) Forschungs GmbH

penelope@gbg.de

+49 6102 7480

Study Officials

• Sibylle Loibl, MD, Prof

  ASCO, ESMO, EORTC-TRAFO, ESGO, DKG, AGO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2013
• First Posted: May 30, 2013
• Study Start: October 30, 2013
• Primary Completion: August 24, 2020
• Study Completion: December 21, 2020
• Last Updated: December 12, 2023
• Results First Posted: December 12, 2023

Record last verified: 2023-11

Locations

AU (1); ES (1); DE (1); IE (1); JP (1); KR (1); GB (1); US (1); CA (1); FR (1)