Neoadjuvant Hormonal Therapy Plus Palbociclib in Operable, Hormone Sensitive and HER2-Negative Primary Breast Cancer

• Sponsor: Kyoto Breast Cancer Research Network (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03969121
• Collaborator: Pfizer (Industry)
• Enrollment: 200
• Locations: 25
• Arms: 2
• Anticipated Duration (Months): 35.5
• Patients Per Site: 8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Female; Hormone Receptor Positive Malignant Neoplasm of Breast	Drug: Palbociclib; Drug: Endocrine therapy	Phase 3

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jul 16, 2019
• Actual Primary Completion Date: Dec 23, 2021
• Anticipated Study Completion Date: Jun 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Placebo + Endocrine therapy Endocrine therapy for 16 weeks plus placebo	Drug: 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.
Active Comparator: Palbociclib + Endocrine therapy Endocrine therapy for 16 weeks plus Palbociclib	Drug: Palbociclib; Palbociclib will be administered orally once a day for 21 days every 28-day cycle followed by 7 days off treatment; Drug: 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.

Outcome Measures

Primary Outcome Measures

1. Pre-operative Endocrine Prognostic Index (PEPI Score) [4 months]

   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.

2. EndoPredict™ EPclin Score [4 months]

   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.

Secondary Outcome Measures

1. Clinical Response Rate [4 months]

   Observing any reduction in largest tumor diameter on clinical breast examination and ultrasound imaging of breast and axilla after 4 months

2. Ki67 change [4 months]

   Drop in Ki67 index to less than or equal to 2.7%

3. pathological response rate [4 months]

   Evaluating the rate of pathological Complete Response based on assessment of surgical specimen

4. Breast conserving rate [4 months]

   Calculating the rate of breast conserving surgery based on the number of each surgery type

5. Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment as Assessed by CTCAE v4.03 [4 months]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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).

1. Able to give written informed consent form

2. 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);

1. 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

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

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

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

5. Prior hematopoietic stem cell or bone marrow transplantation.

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

7. 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.)

8. Known human immunodeficiency virus (HIV) infection

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

10. 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.

11. 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

12. 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.

13. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Monash Health	Clayton		Australia	3168
2	Peter MacCallum Cancer Centre	Melbourne		Australia
3	UNIMED Medical Institute	Hong Kong		Hong Kong
4	Amagasaki General Medical Center	Amagasaki	Hyogo	Japan	660-8550
5	University of Tsukuba Hospital	Tsukuba	Ibaraki	Japan	305-8576
6	Kyushu Cancer Center	Fukuoka		Japan	811-1395
7	Sagara Hospital	Kagoshima		Japan	892-0833
8	Kobe City Medical Center General Hospital	Kobe		Japan	650-0047
9	Kyoto University Hospital	Kyoto		Japan	606-8507
10	Aichi Cancer Center	Nagoya		Japan	464-8681
11	Tazuke Kofukai, Medical Research Institute, Kitano Hospital	Osaka		Japan	530-8480
12	Saitama Cancer Center	Saitama		Japan	362-0806
13	Toranomon Hospital	Tokyo		Japan	105-8470
14	Tokyo Metropolitan Komagome Hospital	Tokyo		Japan	113-8677
15	Cancer Institute Hospital Of JFCR	Tokyo		Japan	135-8550
16	Kyorin University Hospital	Tokyo		Japan	181-8611
17	Kanagawa Cancer Center	Yokohama		Japan	241-8515
18	National Cancer Center, Korea	Gyeonggi-do		Korea, Republic of
19	Seoul National University Bundang Hospital	Seongnam		Korea, Republic of
20	Korea Cancer Center Hospital	Seoul		Korea, Republic of
21	Seoul National University College of Medicine	Seoul		Korea, Republic of
22	Changhua Christian Hospital	Changhua		Taiwan
23	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung		Taiwan
24	National Taiwan University Hospital	Taipei		Taiwan
25	Sun Yat-Sen Cancer Center	Taipei		Taiwan

Sponsors and Collaborators

• Kyoto Breast Cancer Research Network
• Pfizer

Investigators

• Principal Investigator: Masakazu Toi, MD,PhD, Kyoto University, Professor of Breast Surgery Department
• Principal Investigator: Louis WC Chow, MD,PhD, Organisation for Oncology and Translational Research (OOTR)
• Principal Investigator: Takayuki Ueno, MD,PhD, Cancer Institute Hospital of JFCR, Department Director, Breast Surgical Oncology Department

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kyoto Breast Cancer Research Network
• ClinicalTrials.gov Identifier: NCT03969121
• Other Study ID Numbers: OOTR-N016/KBCRN-B-003/HT-PAB
• First Posted: May 31, 2019
• Last Update Posted: Jan 10, 2022
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Kyoto Breast Cancer Research Network: Palbociclib; Breast Cancer; PEPI
• Additional relevant MeSH terms: Breast Neoplasms; Neoplasms; Palbociclib

Study Results

No Results Posted as of Jan 10, 2022