COVID-19 studies are our top priority.

For new and updated trial submissions, we are processing trials as quickly as possible and appreciate your patience. We recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01864746




Registration number
NCT01864746
Ethics application status
Date submitted
14/05/2013
Date registered
30/05/2013
Date last updated
2/02/2021

Titles & IDs
Public 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
Scientific 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"
Secondary ID [1] 0 0
2013-001040-62
Secondary ID [2] 0 0
GBG78/BIG 1-13/NSABP-B-54-I
Universal Trial Number (UTN)
Trial acronym
PENELOPE-B
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Hormonreceptor Positive 0 0
Her2-normal 0 0
Postneoadjuvant Treatment With CDK 4/6 Inhibitor 0 0
CPS-EG Score 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Palbociclib PD-0332991
Treatment: Drugs - Placebo

Experimental: Palbociclib - 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

Placebo Comparator: Placebo - Placebo of palbociclib once daily day 1 to day 21 followed by 7 days off treatment in a28-day cycle for thirteen cycles


Treatment: Drugs: Palbociclib PD-0332991
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

Treatment: Drugs: Placebo
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 code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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)).
Two interim efficacy analyses will be performed in the study. First interim analysis: Safety, early stopping Second interim analysis: Safety, early stopping, sample size adjustment
Timepoint [1] 0 0
Time-to-Event Outcome measure. Final analysis on the primary endpoint and secondary efficacy endpoints (except for OS) Analysis will be conducted when 255 events observed. Assessed until approx. Dec 2020.
Secondary outcome [1] 0 0
iDFS excluding second non-breast cancers - Invasive disease-free survival (iDFS) is defined according to Hudis (J Clin Oncol 2007) as the time period between randomization and first event.
Timepoint [1] 0 0
Time-to-Event Outcome Measure up to 71 months
Secondary outcome [2] 0 0
distant disease free survival (DDFS) - Distant disease free survival (DDFS) is defined as the time period between randomization and diagnosis of first distant breast cancer recurrences.
Timepoint [2] 0 0
Time-to-Event Outcome Measure up to 71 months
Secondary outcome [3] 0 0
overall survival (OS) - Overall survival (OS) is defined as the time period between randomization and death of any cause. An interim OS analysis will be conducted at the time of final iDFS analysis and final OS analysis will be conducted at a later time. In addition Relapse and Mortality data will be collected post study.
Timepoint [3] 0 0
Time-to-Event Outcome Measure up to 71 months - and post study
Secondary outcome [4] 0 0
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) - see above for event definition
Timepoint [4] 0 0
Time-to-Event Outcome Measure up to 71 months
Secondary outcome [5] 0 0
compliance and safety according to NCI-CTCAE Version 4.0 - Descriptive statistics for the 2 treatments will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped.
Timepoint [5] 0 0
2019 and with interim analysis on safety
Secondary outcome [6] 0 0
patients reported outcomes EORTC QLQ C30, • EORTC QLQ BR-23, • EORTC QLQ FA-13 Fatigue, • GAD7 patient self-rating mood scale - Screening, Cycle 1, 3, 5, 7, 9, 11, End of treatment and thereafter every 6 months until 233 events are observed
Timepoint [6] 0 0
Change Outcome up to 71 months
Secondary outcome [7] 0 0
quality-adjusted life years (QALY), health economic outcomes EQ-5D - Screening, Cycle 1, 3, 5, 7, 9, 11, End of treatment and thereafter every 6 months
Timepoint [7] 0 0
Change Outcome Measure up to 71 months
Secondary outcome [8] 0 0
Area under the Curve (AUC), Cmax - Drug-drug interactions (DDI) potential for palbociclib - endocrine combination therapy
In the first 24 patients receiving tamoxifen or anastrozol together with palbociclib/placebo plasma PK samples will be drawn on pre-dose and 2, 4, 6, 8, and 24 hours post-dose for DDI assessment.
In the first 24 patients receiving gosereline and tamoxifen together with palbociclib/placebo, plasma PK samples will be drawn on Cycle 2 and Cycle 3 Days 1 and Day 14 pre-dose for DDI assessment.
In addition in the first 24 patients receiving gosereline and tamoxifen together with palbociclib/placebo, plasma PK samples will be drawn on Cycle 2 and Cycle 3 Days 1 and Day 14 pre-dose for DDI assessment.
Timepoint [8] 0 0
pre-dose, 2, 4, 6, 8, and 24 hours
Secondary outcome [9] 0 0
correlations between exposure and efficacy and/or safety findings - Trough concentrations of PD-0332991 will be collected pre-dose on Day 14 of cycle 1 and 2 for all patients (including letrozol taking patients).
Timepoint [9] 0 0
Pharmacokinetic Outcomes Measure mit Cmax and AUC

Eligibility
Key inclusion criteria
Based on protocol G version 11 dated 04 May 2017

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 lymphnode can be assessed.

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. 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 (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.
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
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, hypo¬magnesemia).

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 (see appendix 21.3)

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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Contact: Australia and New Zealand Breast Cancer Trials Group - Newcastle
Recruitment postcode(s) [1] 0 0
PO Box 155 - Newcastle
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Pennsylvania
Country [2] 0 0
Austria
State/province [2] 0 0
Vienna
Country [3] 0 0
Canada
State/province [3] 0 0
Multiple Locations
Country [4] 0 0
France
State/province [4] 0 0
Paris
Country [5] 0 0
Germany
State/province [5] 0 0
Neu-Isenburg
Country [6] 0 0
Ireland
State/province [6] 0 0
Dublin
Country [7] 0 0
Japan
State/province [7] 0 0
Tokyo
Country [8] 0 0
Korea, Republic of
State/province [8] 0 0
Seoul
Country [9] 0 0
Spain
State/province [9] 0 0
San Sebastián de los Reyes
Country [10] 0 0
United Kingdom
State/province [10] 0 0
London

Funding & Sponsors
Primary sponsor type
Other
Name
German Breast Group
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Pfizer
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
AGO Study Group
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
NSABP Foundation Inc
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Breast International Group
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01864746
Trial related presentations / publications
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.
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. Review.
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.
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.
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. Epub 2007 Sep 4.
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
Gunter von Minckwitz, MD, Prof
Address 0 0
ASCO, AACR, ESMO, DKG, DGGG, AGO, DGS, BIG, BCIRG, St. Gallen Consensus Panel
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications