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出境医 / 临床实验 / Neoadjuvant Hormonal Therapy Plus Palbociclib in Operable, Hormone Sensitive and HER2-Negative Primary Breast Cancer

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

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
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated 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 : July 16, 2019
Estimated Primary Completion Date : November 30, 2021
Estimated Study Completion Date : June 1, 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 4 months ]
    Drop in Ki67 index to less than or equal to 2.7%

  3. pathological response rate [ Time Frame: 4 months ]
    Evaluating the rate of pathological Complete Response based on assessment of surgical specimen

  4. Breast conserving rate [ Time Frame: 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 [ Time Frame: 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
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Elham Fakhrejahani, MD,PhD 0755857861 kbcrn-b-003@kyoto-breast-cancer.org

Locations
Show Show 27 study locations
Sponsors and Collaborators
Kyoto Breast Cancer Research Network
Pfizer
Investigators
Layout table for investigator information
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
Tracking Information
First Submitted Date  ICMJE May 13, 2019
First Posted Date  ICMJE May 31, 2019
Last Update Posted Date May 25, 2021
Actual Study Start Date  ICMJE July 16, 2019
Estimated Primary Completion Date November 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
  • Pre-operative Endocrine Prognostic Index (PEPI Score) [ Time Frame: 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.
  • EndoPredict™ EPclin Score [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
  • Clinical Response Rate [ Time Frame: 4 months ]
    Observing any reduction in largest tumor diameter on clinical breast examination and ultrasound imaging of breast and axilla after 4 months
  • Ki67 change [ Time Frame: 4 months ]
    Drop in Ki67 index to less than or equal to 2.7%
  • pathological response rate [ Time Frame: 4 months ]
    Evaluating the rate of pathological Complete Response based on assessment of surgical specimen
  • Breast conserving rate [ Time Frame: 4 months ]
    Calculating the rate of breast conserving surgery based on the number of each surgery type
  • Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment as Assessed by CTCAE v4.03 [ Time Frame: 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neoadjuvant Hormonal Therapy Plus Palbociclib in Operable, Hormone Sensitive and HER2-Negative Primary Breast Cancer
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Cancer Female
  • Hormone Receptor Positive Malignant Neoplasm of Breast
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • Active Comparator: Placebo + Endocrine therapy
    Endocrine therapy for 16 weeks plus placebo
    Intervention: Drug: Endocrine therapy
  • Active Comparator: Palbociclib + Endocrine therapy
    Endocrine therapy for 16 weeks plus Palbociclib
    Interventions:
    • Drug: Palbociclib
    • Drug: Endocrine therapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 29, 2019) 		200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2022
Estimated Primary Completion Date November 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Elham Fakhrejahani, MD,PhD 0755857861 kbcrn-b-003@kyoto-breast-cancer.org
Listed Location Countries  ICMJE Australia,   Hong Kong,   Japan,   Korea, Republic of,   Taiwan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03969121
Other Study ID Numbers  ICMJE OOTR-N016/KBCRN-B-003/HT-PAB
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Kyoto Breast Cancer Research Network
Study Sponsor  ICMJE Kyoto Breast Cancer Research Network
Collaborators  ICMJE Pfizer
Investigators  ICMJE
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
PRS Account Kyoto Breast Cancer Research Network
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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