Biological and Clinical Effects of Palbociclib With Ovarian Suppression and Letrozole in the Neoadjuvant Treatment of Breast Cancer

• ClinicalTrials.gov Identifier: NCT03628066
• Recruitment Status: Completed
• First Posted: August 14, 2018
• Last Update Posted: April 20, 2022
• Sponsor: NSABP Foundation Inc
• Collaborators: Genomic Health®, Inc.; Pfizer
• Information provided by (Responsible Party): NSABP Foundation Inc

Study Description

Brief Summary:

This study will look at the safety and effectiveness of the combination of palbociclib and letrozole and ovarian suppression for premenopausal patients who have ER-positive/HER2-negative breast cancer that has not yet been treated.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: Letrozole; Drug: Palbociclib; Drug: Goserelin; Diagnostic Test: Oncotype DX Breast Recurrence Score	Phase 2

Detailed Description:

NSABP FB-13 is a phase II, open label study to examine the biological and clinical effect of neoadjuvant endocrine therapy with letrozole, palbociclib and ovarian suppression in premenopausal patients with estrogen-receptor (ER) positive, HER2-negative, early invasive breast cancer.

Premenopausal women newly diagnosed with ER-positive/HER2-negative early breast cancer who are suitable candidates for neoadjuvant endocrine therapy will be invited to join the FB-13 trial. A screening Oncotype DX Breast Recurrence Score® will be performed by Genomic Health, Inc. (GHI) on the diagnostic tissue of consenting patients to verify eligibility.

Patients will be stratified into one of two approximately equal sized cohorts based on baseline Breast Recurrence Score (RS) (cohort 1: patients with RS less than 11 or cohort 2: patients with RS 11 to less than 26).

Patients in both cohorts will receive letrozole 2.5 mg by mouth daily, palbociclib 125 mg by mouth daily for 21 days of a 28 day cycle, and goserelin 3.6 mg subcutaneous injection on Day 1 of each 28 day cycle. At Week 6 of study therapy, patients will have two core-cut biopsies. Patients from both cohorts who have a Ki67 less than 10% level will continue receiving study therapy for a total of 6 cycles. Patients with a persistent Ki67 greater than or equal to 10% at week 6 will permanently discontinue study therapy and begin neoadjuvant chemotherapy or proceed to surgery at the discretion of the treating physician.

Pre-treatment samples and post-surgical samples will be collected and analysed to identify subgroups of patients who may derive the most clinical benefit. The results of the biological analyses may allow a target sensitive population to be selected for future trials. The tissue collected in FB-13 will form an integral part of the primary analyses; so all core biopsies in this trial will be mandated for patients.

Two core-cut biopsies will be collected from each patient at baseline, after 6 weeks of study therapy, and upon completion of study therapy (24 weeks) at the time of definitive surgery.

Blood samples will be collected at baseline, 4 weeks, and at 24 weeks for estrone and estradiol levels to demonstrate ovarian suppression. A 4-week estradiol level in the postmenopausal range will be required to receive further treatment on study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Assessment of the Biological and Clinical Effects of Palbociclib (PD 0332991) With Ovarian Suppression and Letrozole in the Neoadjuvant Treatment of Patients With Premenopausal Estrogen-Receptor Positive/HER2-Negative Primary Breast Cancer
• Actual Study Start Date: October 22, 2018
• Actual Primary Completion Date: November 30, 2020
• Actual Study Completion Date: January 30, 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Arm 1; Oncotype DX Breast recurrence score on diagnostic tissue Daily Letrozole for 24 weeks + Palbociclib daily for 24 weeks + Goserelin weekly for 24 weeks

Drug: Letrozole; Letrozole 2.5 mg by mouth daily for 24 weeks; Other Name: Femara; Drug: Palbociclib; Palbociclib 125mg by mouth daily for 21 days per 28-day cycle (21 days on, 7 days off) for 24 weeks; Other Name: Ibrance; Drug: Goserelin; Goserelin 3.6mg subcutaneous injection x 1 on Day 1 of each 28-day cycle for 24 weeks; Other Name: Zoladex; Diagnostic Test: Oncotype DX Breast Recurrence Score; Prior to assignment to Arm 1 the Oncotype DX diagnostic test will be conducted on diagnostic tissue to assign a recurrence score for stratification to cohort 1 or 2.

Outcome Measures

Primary Outcome Measures :

1. Complete Cell cycle arrest [ Time Frame: From study entry to the time of the 6 week tumor biopsy to assess Ki67, approximately 6 weeks ]
   Percentage of patients with a Ki67 less than 2.7%

Secondary Outcome Measures :

1. Objective response rate [ Time Frame: From study entry to the 24 week clinical assessment/ultrasound, approximately 24 weeks ]
   Objective response rate determined by breast tumor assessment measured by clinical exam and ultrasound
2. Pathologic complete response to study therapy (breast) [ Time Frame: From study entry to time of surgery, generally 3 to 4 weeks after completion of study therapy at approximately 28 weeks ]
   Percentage of patients with absence of invasive cancer in surgical specimens
3. Pathologic complete response to study therapy (breast with nodes) [ Time Frame: From study entry to time of surgery, generally 3 to 4 weeks after completion of study therapy at approximately 28 weeks ]
   Percentage of patients with absence of invasive cancer in surgical specimens
4. Correlation between Oncotype DX Breast Recurrence Score® and clinical Complete Response (cCR) [ Time Frame: From study entry to the 24 week clinical assessment/ultrasound, approximately 24 weeks ]
   Correlation of the Oncotype DX Breast Recurrence Score® with clinical Complete Response
5. Correlation between Oncotype DX Breast Recurrence Score® and pathologic Complete Response (pCR) [ Time Frame: From study entry to time of surgery, generally 3 to 4 weeks after completion of study therapy at approximately 28 weeks ]
   Correlation of the Oncotype DX Breast Recurrence Score® with pathologic Complete Response
6. Correlation between Oncotype DX Breast Recurrence Score® and Complete Cell cycle arrest rate (CCAR) [ Time Frame: From the time of study entry to time of the 6-week tumor biopsy to assess Ki67, approximately 6 weeks ]
   Correlation of the Oncotype DX Breast Recurrence Score® with Complete Cell cycle arrest rate
7. Comparison between surgical intent and surgery received [ Time Frame: From study entry to time of surgery, generally 3 to 4 weeks after completion of study therapy at approximately 28 weeks ]
   Changes between surgical intent declared at study start and actual surgery received after treatment
8. Comparison of estrone levels [ Time Frame: From study entry to the 4 week blood draw, approximately 4 weeks ]
   Compare the estrone level at baseline to that after neoadjuvant treatment
9. Comparison of estradiol levels [ Time Frame: From study entry to the 4 week blood draw, approximately 4 weeks ]
   Compare the estradiol level after neoadjuvant treatment

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients must be premenopausal. Patients with a hysterectomy: menopausal status must be confirmed by estradiol and FSH.
• Operable hormonal receptor (HR) positive (ER/PR greater than or equal to 10%), HER2- negative, invasive early breast cancer, suitable for neoadjuvant AI treatment and ovarian suppression; HR- positive and HER2-negative as determined by American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP ) guidelines.
• Diagnostic breast tissue must have an Oncotype DX Breast Recurrence Score® of less than 26 as determined by Genomic Health, Inc.
• No known severe hypersensitivity reactions to compounds similar to palbociclib or palbociclib excipients or to endocrine treatments.
• A breast tumor with an ultrasound size of at least 2.0 cm.
• Patients must have the ability to swallow oral medication.
• ECOG performance status of 0 or 1.

• At the time of randomization, blood counts performed within 2 weeks prior to randomization must meet the following criteria:

  • ANC must be greater than or equal to 1500/mm3
  • Platelet count must be greater than or equal to 100,000/mm3
  • Hemoglobin must be greater than or equal to 10g/dL.
• INR must be within normal limits of the local laboratory ranges. For laboratories that do not report an ULN for the INR assay, use less than or equal to 1.2 as the value for the ULN.

• The following criteria for evidence of adequate hepatic function performed within 2 weeks prior to study entry must be met:

  • Total bilirubin must be less than or equal to ULN for the lab unless the patient has a bilirubin elevation greater than ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and
  • Alkaline phosphatase must be must be less than or equal to 1.5 x ULN for the lab; and
  • AST and ALT must be less than or equal to 1.5 x ULN for the lab.
• Serum creatinine performed within 2 weeks prior to study entry must be less than or equal to 1.25 x ULN or estimated creatinine clearance greater than or equal to 60 mL/min (as calculated using the method standard for the institutions).

Exclusion Criteria:

• Active hepatitis B or hepatitis C with abnormal liver function tests.
• HIV positive patients receiving antivirals.
• Inflammatory/inoperable breast cancer.
• HER2-positive as determined using ASCO-CAP Guidelines.
• Oncotype Dx Breast Recurrence Score® result on diagnostic breast tissue greater than or equal to 26.
• Prior endocrine therapy for breast cancer.
• Any invasive malignancy within previous 5 years (other than basal cell carcinoma or cervical carcinoma in situ).

• Other nonmalignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow up such as:

  • Active infection or chronic infection requiring chronic suppressive antibiotics;
  • Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small bowel, or other disease or condition significantly affecting gastrointestinal function;
  • Chronic daily treatment with corticosteroids with a dose of greater than or equal to 10 mg/day methylprednisolone equivalent (excluding inhaled steroids);
  • Seizure disorders requiring medication.
• Diagnosis by fine needle aspiration (FNA) alone or excisional biopsy or lumpectomy performed prior to study entry.
• Surgical axillary staging procedure prior to study procedure (with exception of FNA or core biopsy).
• Definitive clinical or radiologic evidence of metastatic disease.
• History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral DCIS treated with radiotherapy or contralateral invasive breast cancer at any time.
• Any treatment, including radiotherapy, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to study entry.

• Use of any medication or substances that are strong inhibitors or inducers of CYP3A isoenzymes. Class III or Class IV myocardial disease as described by the New York Heart Association; a recent history (within 6 months) of myocardial infarction, or symptomatic arrhythmia at the time of randomization.

  • Class III: Patients with cardiac disease resulting in marked limitation of physical activity. Such patients are comfortable at rest. Less than ordinary physical activity that causes fatigue, palpitation, dyspnea, or anginal pain.
  • Class IV: Patients with cardiac disease resulting in inability to perform any physical activity without discomfort. Symptoms of cardiac insufficiency or anginal syndrome may be present even at rest.
• The investigator should assess the patient to determine if she has any psychiatric or addictive disorder or other condition that, in the opinion of the investigator, would preclude her from meeting the study requirements.

Contacts and Locations

Locations

United States, California

Breast Cancer Care Specialist

Fountain Valley, California, United States, 92708

Orange Coast Blood and Cancer Care

Fountain Valley, California, United States, 92708

Saddleback Memorial Medical Center

Laguna Hills, California, United States, 92653

Coast Hematology-Oncology Associates Medical Group

Long Beach, California, United States, 90806

Long Beach Memorial Medical Center

Long Beach, California, United States, 90806

Oncology Hematology Consultants

Long Beach, California, United States, 90806

United States, Illinois

Cancer Care Specialists of Central Illinois

Decatur, Illinois, United States, 62526

United States, South Dakota

Avera Cancer Institute-Sioux Falls

Sioux Falls, South Dakota, United States, 57105

United States, Texas

Lester and Sue Smith Breast Center

Houston, Texas, United States, 77030

United States, West Virginia

West Virginia University

Morgantown, West Virginia, United States, 26506

United States, Wisconsin

Froedtert Hospital

Milwaukee, Wisconsin, United States, 53226

Canada, Quebec

Centre Hospitalier de l'Universite de Montreal

Montreal, Quebec, Canada, H2X-3E4

Jewish General Hospital - Montreal

Montreal, Quebec, Canada, H3T 1E2

McGill University Health Centre-Cedars Cancer Centre

Montréal, Quebec, Canada, H4A 3J1

CHU de Quebec - Hopital de Saint-Sacrement

Quebec City, Quebec, Canada, G1S 4L8

Sponsors and Collaborators

NSABP Foundation Inc

Genomic Health®, Inc.

Pfizer

Investigators

• Principal Investigator: Norman Wolmark, MD; NSABP Foundation Inc

More Information

• Responsible Party: NSABP Foundation Inc
• ClinicalTrials.gov Identifier: NCT03628066
• Other Study ID Numbers: NSABP FB-13
• First Posted: August 14, 2018
• Last Update Posted: April 20, 2022
• Last Verified: April 2022

• 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.: No

Keywords provided by NSABP Foundation Inc:

Ovarian Suppression; Neoadjuvant; Premenopausal; Estrogen-Receptor Positive; HER2-Negative; Primary; Palbociclib; Letrozole; Goserelin; Ki67; Oncotype DX Breast Recurrence Score; Open-Label

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Letrozole; Palbociclib; Goserelin; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Protein Kinase Inhibitors; Antineoplastic Agents, Hormonal