Tamoxifen Citrate or Letrozole with or without Palbociclib in Treating Patients with Stage I-III Invasive Breast Cancer before Surgery
- Patients must have stage I to III histologically confirmed invasive carcinoma of the breast; a minimum tumor size of at least 1.5 cm determined by physical exam or imaging (whichever is larger) is required
- Patients must have histologically confirmed hormone receptor positive (ER and/or progesterone receptor [PR]), human epidermal growth factor receptor 2 (HER2) negative, early invasive breast cancer; ER, PR and HER2 measurements should be performed according to institutional guidelines, in a Clinical Laboratory Improvement Amendments (CLIA)-approved setting in the United States (US) or certified laboratories for non-US regions; cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines; central confirmation is not required for ER, PR, or HER statuses
- Patients with equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines are allowed, as long as the clinician has determined that they should be treated as HER2 negative
- For the window phase: Patients must have histologically confirmed invasive lobular carcinoma or invasive ductal carcinoma; no central confirmation of histological subtype is necessary for enrollment; patients with mixed invasive ductal and lobular carcinoma are eligible and will be stratified as ductal
- For the treatment phase: Patients with any histological subtype are eligible
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Absolute neutrophil count >= 1,500/mm^3
- Platelets >= 100,000/mm^3
- Hemoglobin >= 10 g/dL
- Total serum bilirubin =< upper limit of normal (ULN); or total bilirubin =< 3.0 x ULN with direct bilirubin within normal range in patients with documented Gilbert’s syndrome
- Aspartate amino transferase (AST or serum glutamic oxaloacetic transaminase [SGOT]) and alanine amino transferase (ALT or serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x institutional ULN
- Serum creatinine below institutional upper limit of normal or creatinine clearance >= 60 mL/min/1.73 m^2 for patients with serum creatinine levels above institutional ULN
- Postmenopausal is defined either by age >= 60, prior bilateral oophorectomy, or age < 60 with intact uterus and no spontaneous menses over 12 consecutive months; follicle stimulating hormone (FSH) and luteinizing hormone (LH) will not be utilized to define menopausal status, unless history of prior total hysterectomy; premenopausal patients are eligible to participate; medication-induced amenorrhea will not categorize a patient as post-menopausal; these patients should be treated as pre-menopausal; premenopausal and peri-menopausal patients should receive ongoing treatment with luteinizing hormone-releasing hormone (LHRH) agonists (goserelin or leuprolide); premenopausal patients must be enrolled directly into the treatment phase of the study
- Patient must agree to the required research biopsies at baseline and after the two-week treatment with endocrine therapy in the initial part of the study (“window phase”); or at baseline and after two-week treated with endocrine therapy plus or minus palbociclib for those patients enrolled directly into the treatment phase of the study
- Patients must be able and willing to swallow and retain oral medication without a condition that would interfere with enteric absorption
- Breast imaging should include imaging of the ipsilateral axilla; for subjects with a clinically negative axilla, a sentinel lymph node biopsy will be performed either before or after preoperative therapy at the discretion of the subject’s physicians; for subjects with a clinically positive axilla, a needle aspiration, core biopsy or sentinel lymph node (SLN) procedure will be performed to determine the presence of metastatic disease in the lymph nodes
- Patients with multifocal or multi-centric disease are eligible if the treating clinician has determined the patient should be treated as ER+ and HER2- negative
- Bilateral breast cancers are allowed if the treating clinician has determined the patient should be treated as ER+ and HER2- negative
- Serum or urine pregnancy test must be negative in women judged premenopausal within 7 days of randomization, or in women with amenorrhea of less than 12 months at time of randomization; pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation
- Premenopausal patients must agree to use adequate contraception for the duration of protocol treatment and for 6 months after the last treatment with palbociclib; adequate contraception is defined as one highly effective form (i.e. abstinence, male or female sterilization) OR two effective forms (e.g. non-hormonal intrauterine device [IUD] and condom/occlusive cap with spermicidal foam/gel/film/cream/suppository); hormonal contraceptive methods are not allowed; patients with hormonal IUD in place are eligible provided the hormonal IUD is removed or replaced by a non-hormonal IUD prior to treatment initiation
- Patients with a history of ipsilateral or contralateral ductal carcinoma in situ (DCIS) are eligible
- Patients may concurrently receive bisphosphonates or rank ligand inhibitors while on this study if necessary for treatment or prevention of osteopenia or osteoporosis; prior treatment with LHRH agonists is allowed for premenopausal women; topical vaginal estrogen therapy is allowable
- Ability to understand and the willingness to sign a written informed consent document
- Concurrent therapy with other investigational products
- Prior therapy with any cyclin-dependent kinase (CDK) inhibitor
- Patients with stage IV breast cancer are not eligible; baseline staging to document absence of metastatic disease is not required, however is recommended as determined by institutional practice (in patients where there may be a reasonable suspicion of advanced disease e.g., large tumors, clinically positive axillary lymph nodes, signs and symptoms); if performed, reports of these examinations must be available; examination type for staging, i.e. X-ray, sonography, bone scans, computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET)-CT, is at the discretion of the investigator
- History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib
- Patients receiving any medications or substances that are potent inhibitors or inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) isoenzymes within 7 days of randomization for list of CYP3A inhibitors and inducers
- Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, or psychiatric illness/social situations that would limit compliance with study requirements; ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation
- Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to randomization, irrespective of the method of contraception used, are excluded from this study because the effect of palbociclib on a developing fetus is unknown; breastfeeding must be discontinued prior to study entry
- Patients with a history of malignancy are ineligible except for the following circumstances: * Patients with a history of invasive breast cancer are eligible if they have been disease-free for a minimum of five years * Patients with a malignancy history other than invasive breast cancer are eligible if they have no active malignancy and are deemed by the investigator to be at low risk for recurrence of that malignancy * Patients with the following cancers are eligible: ductal carcinoma in situ of the breast, cervical cancer in situ, and non-metastatic non-melanomatous skin cancers
- Patients on combination antiretroviral therapy, i.e. those who are human immunodeficiency virus (HIV)-positive, are ineligible; HIV testing is not required, but patients must not be known to be HIV-positive
- Patients receiving concurrent exogenous hormone therapy (hormone replacement therapy, oral or any other hormonal contraceptives such as hormonal contraceptive coil are not eligible
- Patients are not eligible if they have previously received endocrine therapy within 5 years prior to diagnosis of the current malignancy; this includes use for prophylactic reasons, including treatment of osteoporosis or cancer prevention with tamoxifen, raloxifene, or aromatase inhibitors (AI)
I. To evaluate the difference in anti-proliferative activity of letrozole versus tamoxifen measured by changes in Ki67 from baseline to research biopsy (day 15) within cohorts of estrogen receptor positive (ER+) breast cancer for patients with invasive lobular and ductal carcinoma. (Window Phase)
II. To evaluate the pathologic complete response (pCR) of endocrine therapy + palbociclib and of endocrine therapy alone in breast cancer patients diagnosed with hormone receptor positive invasive breast cancer. (Treatment Phase)
I. To evaluate the response of endocrine therapy + palbociclib and of endocrine alone in breast cancer patients according to central Preoperative Endocrine Therapy Prognostic Index (PEPI).
II. To determine the clinical response rate, defined as the number of partial and complete responses after preoperative endocrine therapy + palbociclib and of endocrine therapy alone in breast cancer patients diagnosed with hormone receptor positive invasive breast cancer.
III. To characterize safety and tolerability of palbociclib given in combination with endocrine therapy in the preoperative setting.
CORRELATIVE SCIENCE OBJECTIVES:
I. To explore the differences in anti-proliferative activity of letrozole and tamoxifen measured by changes in Ki67 from baseline to research biopsy (day 15) within cohorts of Luminal A (LA) and Luminal (B) invasive breast cancer.
II. To explore the correlation of retinoblastoma (Rb) phosphorylation and % change in Ki67 from baseline to research biopsy (day 15) among patients treated with letrozole and palbociclib.
III. To explore CISTROME findings from research biopsy (day 15) in the subset of invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) treated with tamoxifen, letrozole or letrozole plus palbociclib.
IV. To describe the pathologic complete response (pCR) of endocrine therapy + palbociclib compared to endocrine therapy alone within cohorts of LA and LB invasive breast cancer.
V. To compare whole exome sequencing and copy number findings between pre-treatment and residual tumors.
VI. To describe the association between whole exome sequencing and copy number findings and pCR.
VII. To explore potential biomarkers that may be relevant to palbociclib efficacy. Potential biomarkers include but not are limited to expression of cyclin D1, Rb protein and p16.
VIII. To explore whether molecular features of invasive lobular carcinoma predicts for greater sensitivity to palbociclib when compared to invasive ductal carcinoma. Molecular features of ILC include but are not limited to higher frequency of cyclin D1 amplification, and enrichment for Luminal A subtype when compared to IDC.
IX. To characterize serial changes in immune marker profile in peripheral blood mononuclear cells (PBMCs) among patients treated with endocrine therapy with or without palbociclib.
X. To explore whether induction of changes in the immunosuppressive and/or immune-stimulating immune marker profile in PBMCs correlates immune marker profile changes in the research biopsies.
WINDOW PHASE: Postmenopausal patients are randomized to 1 of 2 arms.
ARM A: Patients receive tamoxifen citrate orally (PO) once daily (QD) for 14 days.
ARM B: Patients receive letrozole PO QD for 14 days.
TREATMENT PHASE: Patients are randomized to 1 of 2 arms.
ARM C: Patients receive palbociclib PO QD on days 1-21. Postmenopausal patients also receive letrozole PO QD on days 1-28. Premenopausal patients also receive tamoxifen citrate PO QD on days 1-28 and gonadotropin-releasing hormone analog intramuscularly (IM) once monthly. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
ARM D: Postmenopausal patients receive letrozole PO QD on days 1-28. Premenopausal patients receive tamoxifen citrate PO QD on days 1-28 and gonadotropin-releasing hormone analog IM once monthly. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up annually for 10 years post-surgery. Patients who do not undergo surgery will be followed up at 30 days.
Trial Phase Phase II
Trial Type Treatment
Dana-Farber Harvard Cancer Center
- Primary ID 16-052
- Secondary IDs NCI-2016-00893
- Clinicaltrials.gov ID NCT02764541