Neoadjuvant Letrozole and Palbociclib in Patients With Stage II-IIIB Breast Cancer, HR+, HER2 -

NCT03819010

Last updated date
Study Location
ICO Badalona
Badalona, Barcelona, 08916, Spain
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Breast Cancer
Sex
Female
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

Patients must meet ALL of the following inclusion criteria to be eligible for enrolment into the study:

1. Female patients over 18 years of age.

2. Patients have been informed about the nature of study, have agreed to participate in the study, and have signed the informed consent form prior to participation in any study-related activities.

3. Premenopausal and postmenopausal women. Premenopausal women must be treated with LHRH analogue since patient pre- registration. Premenopausal or postmenopausal status should have been established before starting study treatment with letrozole plus palbociclib based on the following classification:

1. Postmenopausal status is defined as either:

- Prior bilateral oophorectomy; Or

- Age>60 years; Or

- Age<60 years and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression, and follicle-stimulating hormone (FSH) and estradiol in postmenopausal range.

2. Premenopausal status is defined as all those women who do not meet any of above criteria.

4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.

5. Histologically confirmed infiltrating breast cancer.

6. HR-positive (estrogen receptor [ER]-positive and/or progesterone receptor [PgR]-positive) EBCs (breast cancers that have at least 10% of cells staging positive for ER and/or PgR). ER and/or PgR status will be centrally confirmed by using immunohistochemistry (IHC) testing for an Allred score of 6-8 in at least one of them.

7. Patients with HER2-negative breast cancer through in situ hybridization test (fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], or silver enhanced in situ hybridization [SISH]) or negative immunohistochemical status of 0, 1+, or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required.

8. Ki67 levels ≥ 20% confirmed by IHC testing in a central laboratory.

9. Tumor size > 2,0 cm (T2-4 according to TNM staging system, but always > 2,0 cm) by mammogram, breast ultrasound, or breast magnetic resonance imaging (MRI).

10. Patients must have a measurable disease by mammogram and/or breast ultrasound.

11. Patients with two significant lesions (both larger than 1 cm and with more than 1 cm distance between them) will require tumor sample from both lesions and proper preoperative marking of both. To be registered, both lesions should fulfil inclusion criteria 5 and 6 and both tumor samples will be submitted. Patient with more than 2 significant lesions will not be eligible.

12. Limited node involvement (N0-2, according to TNM staging system), assessed by ultrasound. Sentinel lymph node biopsy or axillary dissection, are allowed.

13. No metastatic disease (M0, according to TNM staging system).

14. Available pre-treatment tissue sample (biopsy) material (formalin- fixed paraffin-embedded (FFPE) for central confirmation and RS evaluation by the Assay.

15. Patients agree to collection of tissue biopsy from the primary breast cancer at the time of study inclusion (screening), at Cycle 1 Day 14 of treatment, and after 24 weeks (surgery), or if experience intolerable side effects, disease progression, or withdraw during 24 weeks of study treatment.

16. No prior chemotherapy, endocrine, or radiation therapy for current disease.

17. Adequate organ function:

1. Hematological: White blood cell (WBC) count ≥ 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5x 109/L, platelet count ≥ 75.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).

2. Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (x ULN) (or total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN in patients with well-documented Gilbert's syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN.

3. Renal: Serum creatinine ≤ 1.5 x ULN.

18. Resolution of all acute toxic effects of prior surgical procedures to grade ≤1 as determined by the NCI CTCAE v.5.0.

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


Patients will be excluded from the study if they meet ANY of the following criteria:


1. Metastatic progression (M1, according to TNM staging system).


2. Substantial nodal involvement (N>2, according to TNM staging system).


3. Non-large tumor (T0-1, according to TNM staging system).


4. Bilateral breast carcinoma.


5. Inflammatory carcinoma (T4d, according to TNM staging system).


6. Patient with multicentric or multifocal (more than 2 lesions) breast cancer.


7. Excisional biopsy of the primary tumor.


8. Known hypersensitivity to any palbociclib excipients.


9. Known hypersensitivity to any letrozole excipients.


10. Patients unable to swallow tablets.


11. Patients have a concurrent malignancy or malignancy within five years of study
enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin
carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk
of recurrence, discussion with the Medical Monitor is required.


12. Previous radiotherapy on the ipsilateral chest wall for the treatment of any other
malignancy.


13. Major surgery (defined as requiring general anesthesia) or significant traumatic
injury within four weeks of start of study treatment, or patients who have not
recovered from the side effects of any major surgery, or patients that may require
major surgery during the course of the study.


14. Have a serious concomitant systemic disorder (i.e., active infection including HIV, or
cardiac disease) incompatible with the study (at the discretion of investigator).


15. Patients with an active bleeding diathesis, previous history of bleeding diathesis, or
anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon
as it is used as prophylaxis intention).


16. History of malabsorption syndrome or other condition that would interfere with enteral
absorption.


17. Chronic daily treatment with corticosteroids with a dose of ≥ 10mg/day
methylprednisolone equivalent (excluding inhaled steroids).


18. QTc interval > 480 msec on basal assessments, personal history of long or short QT
syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes
(TdP).


19. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging
drug (i.e., hypocalcemia, hypokalemia, or hypomagnesemia).


20. Participation in the treatment phase of an interventional trial within 30 days prior
to study treatment start.

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Breast CancerNeoadjuvant Endocrine Therapy, Palbociclib, Avelumab in Estrogen Receptor Positive Breast Cancer
NCT03573648
  1. Washington, District of Columbia
  2. Baltimore, Maryland
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Breast CancerNeoadjuvant Letrozole and Palbociclib in Patients With Stage II-IIIB Breast Cancer, HR+, HER2 -
NCT03819010
  1. Badalona, Barcelona
  2. Madrid,
  3. Valencia,
  4. Oporto,
Female
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE Neoadjuvant Letrozole and Palbociclib in Patients With Stage II-IIIB Breast Cancer, HR+, HER2 -
Official Title  ICMJE Neoadjuvant Letrozole + Palbociclib in Patients With II-IIIB BC,HR+, HER2-, Phenotype and Pretreatment Recurrence Score(RS):18-25 or 26-100 by Oncotype DX Breast RS Assay.Analysis of RS and Pathological Changes at Surgery
Brief Summary This is an international, multicenter, open-label, non-comparative, Simon´s two-stage design, phase II clinical trial.
Detailed Description

Primary objective:

To explore after 6 months of treatment the ability of palbociclib in combination with letrozole to induce global molecular changes measured by either the Oncotype DX Breast Recurrence Score® (the "Assay") test result at surgery (post-treatment Recurrence Score® (RS) result), or pathological Complete Response (pCR) in patients with aggressive luminal tumors (pre-treatment RS result 18-25 or 26-100, and Ki67? 20).

Secondary objectives:

BIOLOGY

  • To explore the ability of palbociclib in combination with letrozole to induce global molecular changes measured by post-treatment RS result, in patients with aggressive luminal tumors (pre-treatment RS result 18-25 and Ki67? 20) after 6 months of treatment.
  • To explore the ability of palbociclib in combination with letrozole to induce global molecular reduction measured by either the post-treatment RS result, and/or Residual Cancer Burden (RCB), and/or Ki67 in patients with aggressive luminal tumors (pre-treatment RS result 18-25 or 26-100 and Ki67 ? 20) after 6 months of treatment.
  • To verify the ability of palbociclib in combination with letrozole to induce global molecular reduction (measured as either post-treatment RS?25 or RCB score of 0-I) in >35% of patients in cohort B with pre-treatment RS 26-100;
  • To verify the ability of palbociclib in combination with letrozole to induce increase in RS result (measured as post-treatment RS 26-100) in <3% of patients in cohort A with pre-treatment RS 18-25;
  • To evaluate the concordance rate between the RCB score (0- I vs. II-III) and the post-treatment RS result in both cohorts of patients after treatment with palbociclib in combination with letrozole;
  • To evaluate the concordance rate between the preoperative endocrine prognostic index (PEPI) score and post-treatment RS result in both cohorts of patients after treatment with palbociclib in combination with letrozole;
  • To evaluate the concordance rate between the pCR and the post-treatment RS result in both cohorts of patients after treatment with palbociclib in combination with letrozole;
  • To determine the change in RS result as measured by median absolute value or median percentage after 6 months of treatment: from pre-treatment RS 18-25 to post-treatment RS 0-17 for patients in cohort A and from pre-treatment RS 26-100 to post-treatment RS?25 for patients in cohort B.

EFFICACY

  • To determine the Overall Response Rate (ORR) of patients treated with palbociclib in combination with letrozole.
  • To evaluate the Maximum Tumor Shrinkage of palbociclib in combination with letrozole.
  • To determine the rate of breast conserving surgery.

SAFETY

? To assess the safety and tolerability of palbociclib in combination with letrozole.

A two-stage Simon's statistical design will be used for both cohorts (minimax design in co-hort B and optimal design in cohort A). A total of 66 patients will be enrolled into this trial, N=33 patients in cohort with high-risk tumors (Cohort B: pre-treatment RS>25) and N=33 patients in cohort with intermediate-risk tumors (Cohort A: pre-treatment RS18-25).

The accrual goal will be of 26 patients (N=13 patients in each cohort) during the first stage. The interim analysis has been planned after 15 patients (cohort B) and 9 patients (cohort A) will be available for biological response evaluation, and in case of positive findings, the trial will recruit additional 40 patients (N=20 patients in each cohort).

  • The study would be defined as positive at final analysis in the cohort B (pre-treatment RS>25), if 8 or more than 8 patients with biological signal (post-treatment RS?25) are observed (?28.6%) among 28 evaluable patients.
  • The study would be defined as positive at final analysis in the cohort A (pre-treatment RS18-25), if 25 or more than 25 patients with biological stabilization (post-treatment RS?25) are observed (?89.3%) among 28 evaluable patients.

Study treatment management

After signing the informed consent form (ICF) and confirmed pre- eligibility, patients will be pre-registered in the study. A tissue biopsy from the primary breast cancer has to be provided at screening and will be used to perform central confirmation of Ki67 levels and HR status, as well as central assessment of RS. Pre-registered patients can receive up to 4 weeks of letrozole before inclusion; pre-menopausal patients will require to combine it with a Luteinizing Hormone-Releasing Hormone (LHRH) analogue. Patients are eligible to enter one of the two cohorts according to RS assessment as follow:

  • Cohort A: patients with pre-treatment RS 18-25;
  • Cohort B: patients with pre-treatment RS 26-100. Patients with pre-treatment RS 0-17 will be considered not eligible. Patients allocated to the cohort A or B will receive 24 weeks of palbociclib (for 21 days every 4 weeks) in combination with letrozole (once daily, beginning on day 1 and continuing through day 28 of every 28-day cycle). Premenopausal women must also be treated with an LHRH analogue during the treatment phase.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
This is an international, multicenter, open-label, non-comparative, Simon´s two-stage design, phase II clinical trial.
Masking: None (Open Label)
Masking Description:
Two arms of patients (according to Recurrence Score results), but both arms will be treated with the same treatment
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: Pre treatment Recurrence Score:18-25 Letrozole + Palbociclib
    Letrozole(2,5 mg/day during 28 days of each Cycle) + Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer for patients with pre-treatment recurrence Score of 18-25
    Other Name: None othe intervention name
  • Drug: Pre treatment Recurrence Score:26-100 Letrozole + Palbociclib
    Letrozole(2,5 mg/day during 28 days of each Cycle) + Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer for patients with pre-treatment recurrence Score of 26-100
    Other Name: None othe intervention name
Study Arms  ICMJE
  • Active Comparator: Pre treatment Recurrence Score:18-25 Letrozole + Palbociclib
    Letrozole (2,5 mg/day during 28 days of each Cycle) + Palbociclib (125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer interventions: Letrozol (2,5 mg/day during 28 days of each Cycle)+ Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer
    Intervention: Drug: Pre treatment Recurrence Score:18-25 Letrozole + Palbociclib
  • Active Comparator: Pre treatment Recurrence Score:26-100 Letrozole + Palbociclib
    Letrozole (2,5 mg/day during 28 days of each Cycle) + Palbociclib (125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer interventions: Letrozol (2,5 mg/day during 28 days of each Cycle)+ Palbociclib(125mg/day during 21 days of each cycle of 28 days) as neoadjuvant treatment during 6 cycles before surgery of Breast Cancer
    Intervention: Drug: Pre treatment Recurrence Score:26-100 Letrozole + Palbociclib
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 Completed
Actual Enrollment  ICMJE
 (submitted: January 25, 2019)
66
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 31, 2019
Actual Primary Completion Date July 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

IInclusion criteria

Patients must meet ALL of the following inclusion criteria to be eligible for enrolment into the study:

  1. Female patients over 18 years of age.
  2. Patients have been informed about the nature of study, have agreed to participate in the study, and have signed the informed consent form prior to participation in any study-related activities.
  3. Premenopausal and postmenopausal women. Premenopausal women must be treated with LHRH analogue since patient pre- registration. Premenopausal or postmenopausal status should have been established before starting study treatment with letrozole plus palbociclib based on the following classification:

    1. Postmenopausal status is defined as either:

      • Prior bilateral oophorectomy; Or
      • Age>60 years; Or
      • Age<60 years and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression, and follicle-stimulating hormone (FSH) and estradiol in postmenopausal range.
    2. Premenopausal status is defined as all those women who do not meet any of above criteria.
  4. Eastern Cooperative Oncology Group (ECOG) performance status ? 1.
  5. Histologically confirmed infiltrating breast cancer.
  6. HR-positive (estrogen receptor [ER]-positive and/or progesterone receptor [PgR]-positive) EBCs (breast cancers that have at least 10% of cells staging positive for ER and/or PgR). ER and/or PgR status will be centrally confirmed by using immunohistochemistry (IHC) testing for an Allred score of 6-8 in at least one of them.
  7. Patients with HER2-negative breast cancer through in situ hybridization test (fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], or silver enhanced in situ hybridization [SISH]) or negative immunohistochemical status of 0, 1+, or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required.
  8. Ki67 levels ? 20% confirmed by IHC testing in a central laboratory.
  9. Tumor size > 2,0 cm (T2-4 according to TNM staging system, but always > 2,0 cm) by mammogram, breast ultrasound, or breast magnetic resonance imaging (MRI).
  10. Patients must have a measurable disease by mammogram and/or breast ultrasound.
  11. Patients with two significant lesions (both larger than 1 cm and with more than 1 cm distance between them) will require tumor sample from both lesions and proper preoperative marking of both. To be registered, both lesions should fulfil inclusion criteria 5 and 6 and both tumor samples will be submitted. Patient with more than 2 significant lesions will not be eligible.
  12. Limited node involvement (N0-2, according to TNM staging system), assessed by ultrasound. Sentinel lymph node biopsy or axillary dissection, are allowed.
  13. No metastatic disease (M0, according to TNM staging system).
  14. Available pre-treatment tissue sample (biopsy) material (formalin- fixed paraffin-embedded (FFPE) for central confirmation and RS evaluation by the Assay.
  15. Patients agree to collection of tissue biopsy from the primary breast cancer at the time of study inclusion (screening), at Cycle 1 Day 14 of treatment, and after 24 weeks (surgery), or if experience intolerable side effects, disease progression, or withdraw during 24 weeks of study treatment.
  16. No prior chemotherapy, endocrine, or radiation therapy for current disease.
  17. Adequate organ function:

    1. Hematological: White blood cell (WBC) count ? 3.0 x 109/L, absolute neutrophil count (ANC) ? 1.5x 109/L, platelet count ? 75.0 x109/L, and hemoglobin ? 10.0 g/dL (? 6.2 mmol/L).
    2. Hepatic: Bilirubin ? 1.5 times the upper limit of normal (x ULN) (or total bilirubin ? 3.0 x ULN or direct bilirubin ? 1.5 x ULN in patients with well-documented Gilbert's syndrome); alkaline phosphatase (ALP) ? 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ? 3 times ULN.
    3. Renal: Serum creatinine ? 1.5 x ULN.
  18. Resolution of all acute toxic effects of prior surgical procedures to grade ?1 as determined by the NCI CTCAE v.5.0.

Exclusion criteria

Patients will be excluded from the study if they meet ANY of the following criteria:

  1. Metastatic progression (M1, according to TNM staging system).
  2. Substantial nodal involvement (N>2, according to TNM staging system).
  3. Non-large tumor (T0-1, according to TNM staging system).
  4. Bilateral breast carcinoma.
  5. Inflammatory carcinoma (T4d, according to TNM staging system).
  6. Patient with multicentric or multifocal (more than 2 lesions) breast cancer.
  7. Excisional biopsy of the primary tumor.
  8. Known hypersensitivity to any palbociclib excipients.
  9. Known hypersensitivity to any letrozole excipients.
  10. Patients unable to swallow tablets.
  11. Patients have a concurrent malignancy or malignancy within five years of study enrollment with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required.
  12. Previous radiotherapy on the ipsilateral chest wall for the treatment of any other malignancy.
  13. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within four weeks of start of study treatment, or patients who have not recovered from the side effects of any major surgery, or patients that may require major surgery during the course of the study.
  14. Have a serious concomitant systemic disorder (i.e., active infection including HIV, or cardiac disease) incompatible with the study (at the discretion of investigator).
  15. Patients with an active bleeding diathesis, previous history of bleeding diathesis, or anti-coagulation treatment (the use of low molecular weight heparin is allowed as soon as it is used as prophylaxis intention).
  16. History of malabsorption syndrome or other condition that would interfere with enteral absorption.
  17. Chronic daily treatment with corticosteroids with a dose of ? 10mg/day methylprednisolone equivalent (excluding inhaled steroids).
  18. QTc interval > 480 msec on basal assessments, personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
  19. Uncontrolled electrolyte disorders that can compound the effects of a QTc-prolonging drug (i.e., hypocalcemia, hypokalemia, or hypomagnesemia).
  20. Participation in the treatment phase of an interventional trial within 30 days prior to study treatment start.
Sex/Gender  ICMJE
Sexes Eligible for Study:Female
Gender Based Eligibility:Yes
Gender Eligibility Description:Pre and post menopausal females
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Portugal,   Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03819010
Other Study ID Numbers  ICMJE MedOPP199
2018-001702-28 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD:Yes
Plan Description:20 hospital will participate at this trial: 17 sites at Spain and 3 at Portugal
Supporting Materials:Study Protocol
Supporting Materials:Statistical Analysis Plan (SAP)
Supporting Materials:Informed Consent Form (ICF)
Supporting Materials:Clinical Study Report (CSR)
Time Frame:The trial separate 2 stage: Stage I it will be radomized 26 patients (20 Sites) from January 2019 to June2019 and Stage II: 40 patients (25 sites) from February 2020 to July 2020.
Access Criteria:patient should be randomized od Data base of hospitals
Responsible Party MedSIR
Study Sponsor  ICMJE MedSIR
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Principal Investigator:Antonio Llombart, PdHMedSIR
PRS Account MedSIR
Verification Date January 2019

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