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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03969121




Registration number
NCT03969121
Ethics application status
Date submitted
13/05/2019
Date registered
31/05/2019
Date last updated
12/08/2020

Titles & IDs
Public title
Neoadjuvant Hormonal Therapy Plus Palbociclib in Operable, Hormone Sensitive and HER2-Negative Primary Breast Cancer
Scientific title
A Phase III Randomized, Double-Blind, Neoadjuvant Study of Hormonal Therapy Plus Palbociclib Versus Hormonal Therapy Plus Placebo in Women With Operable, Hormone Sensitive and HER2-Negative Primary Breast Cancer
Secondary ID [1] 0 0
OOTR-N016/KBCRN-B-003/HT-PAB
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer Female 0 0
Hormone Receptor Positive Malignant Neoplasm of Breast 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
Treatment: Drugs - Endocrine therapy

Active Comparator: Placebo + Endocrine therapy - Endocrine therapy for 16 weeks plus placebo

Active Comparator: Palbociclib + Endocrine therapy - Endocrine therapy for 16 weeks plus Palbociclib


Treatment: Drugs: Palbociclib
Palbociclib will be administered orally once a day for 21 days every 28-day cycle followed by 7 days off treatment

Treatment: Drugs: Endocrine therapy
Pre- and peri-menopausal women will be receiving Ovarian Function Suppression (OFS) by either leuprorelin subcutaneous 3.75 mg q28days or goserelin subcutaneous 3.6 mg q28days plus tamoxifen 20 mg QD in 28-day cycles. Post-menopausal women will receive letrozole 2.5 mg QD in 28-day cycles.

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

Outcomes
Primary outcome [1] 0 0
Pre-operative Endocrine Prognostic Index (PEPI Score) - The PEPI score is derived from four factors assigned a numerical score following neoadjuvant endocrine therapy, ( including Ki67 expression in the surgical specimen, pathologic tumor size, lymph node status, and estrogen receptor (ER) level).
The PEPI score is the sum of each component score and shows the risk points for relapse-free survival. PEPI=0 means low risk. PEPI= 1 to 3 means intermediate risk .
PEPI more than 4 means high risk.
Timepoint [1] 0 0
4 months
Primary outcome [2] 0 0
EndoPredictâ„¢ EPclin Score - EndoPredict is a multigene test used to predict the risk of distant recurrence of early stage, ER positive ,HER-2 Negative invasive breast cancer. EndoPredict Clinical Score (EP clin ) categorizes patinets into low and high risk groups.Combination of the 12-Gene Molecular Score, tumor stage and lymph node status, generating an EPclin Risk Score.The EPclin Risk Score is calculated, according to the model, as:
EPclin Risk Score = (0.35 * tumor size) + (0.64 * lymph node status) + (0.28 * 12-Gene Molecular Score) EPclin Risk Scores from 1.0 through 3.3 shows low risk of recurrencein 10 years.EPclin Risk Scores from 3.4 through 6.0 shows high risk of recurrence in 10 years.
Timepoint [2] 0 0
4 months
Secondary outcome [1] 0 0
Clinical Response Rate - Observing any reduction in largest tumor diameter on clinical breast examination and ultrasound imaging of breast and axilla after 4 months
Timepoint [1] 0 0
4 months
Secondary outcome [2] 0 0
Ki67 change - Drop in Ki67 index to less than or equal to 2.7%
Timepoint [2] 0 0
4 months
Secondary outcome [3] 0 0
pathological response rate - Evaluating the rate of pathological Complete Response based on assessment of surgical specimen
Timepoint [3] 0 0
4 months
Secondary outcome [4] 0 0
Breast conserving rate - Calculating the rate of breast conserving surgery based on the number of each surgery type
Timepoint [4] 0 0
4 months
Secondary outcome [5] 0 0
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment as Assessed by CTCAE v4.03 - Type, incidence, severity (as graded by National Cancer Institute - Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.03), seriousness and relationship to study medications of adverse events (AE) and any laboratory abnormalities
Timepoint [5] 0 0
4 months

Eligibility
Key inclusion criteria
1. Pre/peri- or post-menopausal women 18 years and older (or local legal age, whichever
is higher)

2. Primary tumor greater than 15 mm in diameter

3. Histologically proven invasive breast cancer

4. Positive hormone receptor (ER and/or PgR =1% in proportion of positive staining score)

5. Negative HER-2 receptor (based on 2018 ASCO/CAP Guideline)

6. Ki67 index equal to or greater than 14% (Ki67 = 14%) by central assessment using
actual or virtual slides

7. Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 1

8. No previous history of radiotherapy or systemic therapy including chemotherapy and
hormone therapy for breast cancer

9. Laboratory values must be as follows:

Absolute neutrophil count: = 1,500/mm3

Platelets: = 100,000/mm3

Hemoglobin: = 9 g/dL

Bilirubin: = 1.5 × upper limits of normal (ULN)

Serum Creatinine: = 1.5 × ULN

Alkaline phosphatase: = 2 × ULN

AST and ALT: = 2 × ULN

Cardiac function: Normal finding of Electrocardiogram (ECG) QTc = 480 msec (based on
the mean value of the triplicate ECGs).

10. Able to give written informed consent form

11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests, and other study procedures
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Male

2. Locally advanced breast cancer ( Any T4 or Any N2, N3), or distant metastasis

3. Multicentric breast cancer (Note: Multifocal breast cancer,located in one quadrant/are
is eligible)

4. Prior treatment with chemotherapy, radiotherapy and/or endocrine therapy

5. Previous use of SERMs such as raloxifene.

6. Prior therapy with any CDK4/6 inhibitor or with everolimus, or any agent whose
mechanism of action is to inhibit the PI3K-mTOR pathway.

7. Prior history of other malignancy within 5 years of study entry, aside from basal cell
carcinoma of the skin or carcinoma-in-situ of the uterine cervix

8. Major surgery within 3 weeks of first study treatment

9. Patients treated within the last 7 days prior to randomization with:

- Food or drugs that are known strong and moderate CYP3A4 inhibitors (e.g.,
amprenavir, aprepitant, atazanavir, boceprevir, casopitant, cimetidine,
ciprof-loxacin, clarithromycin, conivaptan, cobicistat, crizotinib, cyclosporine,
da-runavir, diltiazem, dronedarone, elvitegravir, erythromycin, fluconazole,
fosamprenavir, imatinib, indinavir, isavuconazole, istradefylline,
itraconazole,ketoconazole, letermovir, lopinavir, mibefradil, miconazole,
nefazodone, nelfinavir, nilotinib, posaconazole, ritonavir, saquinavir,
schisandra sphenan-thera extract, telaprevir, telithromycin, tofisopam,
verapamil, voriconazole, and grapefruit, grapefruit juice or any product
containing grapefruit);

- Drugs that are known strong and moderate CYP3A4 inducers (e.g., bosentan,
carbamazepine, efavirenz, etravirine, modafinil, phenobarbital, phenytoin,
ri-fampin, rifapentin, and St. John's wort);

10. Any of the following in the previous 6 months of randomization: myocardial
in-farction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version
4.03 grade = 2, atrial fibrillation of any grade, coronary/peripheral artery bypass
graft, symptomatic congestive heart failure, cerebrovascular accident in-cluding
transient ischemic attack, or symptomatic pulmonary embolism

11. Family or personal history of long or short QT syndrome, Brugada syndrome or known
history of QTc prolongation, or Torsade de Pointes (TdP).

12. Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypomag-nesemia)
that can compound the effects of a QTc-prolonging drug.

13. Active inflammatory bowel disease or chronic diarrhea. Short bowel syndrome. Upper
gastrointestinal surgery including gastric resection.

14. Prior hematopoietic stem cell or bone marrow transplantation.

15. Known abnormalities in coagulation such as bleeding diathesis, or treatment with
anticoagulants precluding subcutaneous injections of leuprorelin or goserelin.

16. Hepatitis B and/or hepatitis C carriers (Patients with HBsAg+ or HBV-DNA+ who need
antiviral treatment during any anti-cancer therapy based on guidelines are excluded
even if the patient's hepatic function is normal. Patients with HCVAb+, whose HCV-RNA
is positive (+) are excluded.)

17. Known human immunodeficiency virus (HIV) infection

18. Known hypersensitivity to anti-aromatase drugs, tamoxifen or any cell cycle
in-hibitor.

19. Patients who are pregnant or lactating. Patients of childbearing potential and/or her
partner who are unwilling or unable to use a method of highly effective non-hormonal
contraception throughout the study and continue for at least 21 days in patients after
the last dose of investigational drug.

20. Other severe acute or chronic medical or psychiatric condition, or laboratory
ab-normality that would impart, in the judgment of the investigator, excess risk
as-sociated with study participation or study drug administration, or which, in the
judgment of the investigator, would make the patient inappropriate for entry into this
study

21. Patients who are investigational site staff members or relatives of those site staff
OOTR-N016/KBCRN-B-003/HT-PAB Protocol (version 1.2 dated Oct 11, 2018) 24 members or
patients who are the sponsor employees directly involved in the con-duct of the trial.

22. Participation in other studies involving investigational drug (s) (Phases 1-4) within
2 weeks before randomization and/or until a visit at 4 weeks (+7 days) after
operation.

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
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)
Recruitment hospital [1] 0 0
Monash Health - Clayton
Recruitment hospital [2] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 0 0
3168 - Clayton
Recruitment postcode(s) [2] 0 0
- Melbourne
Recruitment outside Australia
Country [1] 0 0
Hong Kong
State/province [1] 0 0
Hong Kong
Country [2] 0 0
Japan
State/province [2] 0 0
Hyogo
Country [3] 0 0
Japan
State/province [3] 0 0
Ibaraki
Country [4] 0 0
Japan
State/province [4] 0 0
Fukuoka
Country [5] 0 0
Japan
State/province [5] 0 0
Kagoshima
Country [6] 0 0
Japan
State/province [6] 0 0
Kobe
Country [7] 0 0
Japan
State/province [7] 0 0
Kyoto
Country [8] 0 0
Japan
State/province [8] 0 0
Nagoya
Country [9] 0 0
Japan
State/province [9] 0 0
Osaka
Country [10] 0 0
Japan
State/province [10] 0 0
Saitama
Country [11] 0 0
Japan
State/province [11] 0 0
Tokyo
Country [12] 0 0
Japan
State/province [12] 0 0
Yokohama
Country [13] 0 0
Korea, Republic of
State/province [13] 0 0
Gyeonggi-do
Country [14] 0 0
Korea, Republic of
State/province [14] 0 0
Seongnam
Country [15] 0 0
Korea, Republic of
State/province [15] 0 0
Seoul
Country [16] 0 0
Korea, Republic of
State/province [16] 0 0
Suwon
Country [17] 0 0
Taiwan
State/province [17] 0 0
Changhua
Country [18] 0 0
Taiwan
State/province [18] 0 0
Kaohsiung
Country [19] 0 0
Taiwan
State/province [19] 0 0
Taipei

Funding & Sponsors
Primary sponsor type
Other
Name
Kyoto Breast Cancer Research Network
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Pfizer
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
The study is a randomized, double blind, placebo controlled, Phase 3 clinical trial with the
primary objective of demonstrating the efficacy of palbociclib in combination with Endocrine
therapy over Endocrine therapy alone measured by PEPI and EndoPredictâ„¢ EPclin Score in women
with operable HR+, HER2 negative breast cancer . The Clinical Response Rate, drop in Ki67
index = 2.7% and Breast conserving rate will be compared between two arms.
Trial website
https://clinicaltrials.gov/show/NCT03969121
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Masakazu Toi, MD,PhD
Address 0 0
Kyoto University, Professor of Breast Surgery Department
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Elham Fakhrejahani, MD,PhD
Address 0 0
Country 0 0
Phone 0 0
0755857861
Fax 0 0
Email 0 0
kbcrn-b-003@kyoto-breast-cancer.org
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03969121