Clinical trial NCT03969121: Neoadjuvant Hormonal Therapy Plus Palbociclib in Operable, Hormone Sensitive and HER2-Negative Primary Breast Cancer
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer Female
Hormone Receptor Positive Malignant Neoplasm of Breast
Keywords: Palbociclib
Breast Cancer
PEPI
Lead sponsor: Kyoto Breast Cancer Research Network
Sponsor class: OTHER
Collaborators: name: Pfizer
First posted: 2019-05-31
Enrollment: 141
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 EndoPredict™ 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.


Eligibility criteria: 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

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.

Primary outcomes:
measure: Pre-operative Endocrine Prognostic Index (PEPI Score)
timeFrame: 4 months
measure: EndoPredict™ EPclin Score
timeFrame: 4 months
Secondary outcomes:
measure: Clinical Response Rate
timeFrame: 4 months
measure: Ki67 change
timeFrame: 4 months
measure: pathological response rate
timeFrame: 4 months
measure: Breast conserving rate
timeFrame: 4 months
measure: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment as Assessed by CTCAE v4.03
timeFrame: 4 months
Other outcomes:
Locations:
city: Clayton
country: Australia
facility: Monash Health
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
city: Hong Kong
country: Hong Kong
facility: UNIMED Medical Institute
city: Amagasaki
country: Japan
facility: Amagasaki General Medical Center
state: Hyogo
city: Tsukuba
country: Japan
facility: University of Tsukuba Hospital
state: Ibaraki
city: Fukuoka
country: Japan
facility: Kyushu Cancer Center
city: Kagoshima
country: Japan
facility: Sagara Hospital
city: Kobe
country: Japan
facility: Kobe City Medical Center General Hospital
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Nagoya
country: Japan
facility: Aichi Cancer Center
city: Osaka
country: Japan
facility: Tazuke Kofukai, Medical Research Institute, Kitano Hospital
city: Saitama
country: Japan
facility: Saitama Cancer Center
city: Tokyo
country: Japan
facility: Toranomon Hospital
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Komagome Hospital
city: Tokyo
country: Japan
facility: Cancer Institute Hospital Of JFCR
city: Tokyo
country: Japan
facility: Kyorin University Hospital
city: Yokohama
country: Japan
facility: Kanagawa Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: National Cancer Center, Korea
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Korea Cancer Center Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University College of Medicine
city: Changhua
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Sun Yat-Sen Cancer Center
Study officials:
affiliation: Kyoto University, Professor of Breast Surgery Department
name: Masakazu Toi, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Organisation for Oncology and Translational Research (OOTR)
name: Louis WC Chow, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cancer Institute Hospital of JFCR, Department Director, Breast Surgical Oncology Department
name: Takayuki Ueno, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: