Palbociclib in Treating Patients With Metastatic HER-2 Positive Breast Cancer With Brain Metastasis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate if the study drug palbociclib has anti-tumor activity against the breast cancer that has spread to the brain and also to determine the overall radiographic response rate in the CNS. Palbociclib is an anti-cancer medication that has been shown to stop cancer cells from growing. It has been approved in hormone positive breast cancer, along with other hormone therapies and has been found to be effective. The preclinical studies suggest that the drug may also have activity in other types of breast cancer, such as HER2 positive breast cancer. The purpose of this study is to see if the study drug is effective in patients with brain metastasis, who have HER2-positive breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the radiographic response rate in the central nervous system (CNS) in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib. SECONDARY OBJECTIVES: I. To determine the progression-free survival (PFS) and overall survival (OS) in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib. II. To determine time to CNS progression in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib. III. To determine systemic overall response rate (ORR) in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib. IV. To determine the safety and tolerability of palbociclib in patients with and HER2-positive breast cancer. TERTIARY OBJECTIVES: I. To evaluate circulating tumor deoxyribonucleic acid (DNA) at baseline, 2 month and 4 months; particularly to assess cyclin D1 aberrations, and if this is predictive of responses. II. To evaluate genomic landscape of available CNS and non-CNS tumors, and describe any discordance. III. To evaluate cognitive function and quality of life at baseline, 2 and 4 months in patients receiving palbociclib. OUTLINE: Patients receive palbociclib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with HER2 positive breast cancer may also receive trastuzumab intravenously (IV) as standard of care concurrently with palbociclib. After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months, and then every 6 months for up to 3 years.

Official Title
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A Phase II Single Arm Study of Palbociclib in Patients With Metastatic HER2-positive Breast Cancer With Brain Metastasis

Conditions
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Breast Carcinoma Metastatic in the Brain, Estrogen Receptor Negative, HER2/Neu Negative, HER2/Neu Positive, Progesterone Receptor Negative, Recurrent Breast Carcinoma, Stage IV Breast Cancer

Intervention / Treatment
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* Procedure: Cognitive Assessment
* Drug: Palbociclib
* Procedure: Quality-of-Life Assessment
* Biological: Trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed HER2-positive metastatic breast cancer (estrogen and progesterone receptor 0%, HER-2 3+ by immunohistochemistry (IHC); if IHC score of 2, fluorescence in situ hybridization (FISH) ratio must be greater than 2.0; if FISH less than 2.0, HER2 copy number must be greater than 6; NOTE: Brain lesions are not required to have pathologic confirmation Patients should not have received > 2 lines of chemotherapy for metastatic disease Patients must have a life expectancy of at least 12 weeks at the time of registration Eastern Cooperative Oncology Group (ECOG) performance status >= 2 Measurable disease in the brain, defined as at least 1 lesion measuring >= 5 mm on imaging at the time of registration If patients are on corticosteroids, they must have been on a stable or decreasing dose >= 5 days prior to obtaining their baseline gadolinium (Gd)-magnetic resonance imaging (MRI) of brain; this MRI is to be obtained within 28 days of registration; NOTE: If patient needs escalation of steroids prior to therapy, or are on unstable doses of steroids they are not eligible Patients who underwent neurosurgery (NSGY) or stereotactic radiosurgery (SRS) to a brain lesion must have a new measureable lesion; NOTE: SRS may be done to a lesion that will not be used for response evaluation and should be done > 2 weeks prior to registration; any NSGY procedure must have been completed > 3 weeks prior to registration Patients must not have received systemic therapy within 2 weeks of initiating palbociclib; NOTE: For the HER2-positive cohort, patients on trastuzumab can remain on the drug; no break or washout period required; however, lapatinib, ado-trastuzumab-emtansine, and pertuzumab are prohibited and a minimum wash out period of 2 weeks is required Patients must exhibit adequate bone marrow, liver, and renal function, within 14 days prior to registration, defined as: Absolute neutrophil count (ANC) >= 1,000/mm^3 (growth factor support is permitted) Platelets >= 100,000/mm^3 (may be reached by transfusion) Hemoglobin >= 10 gm/dl (may be reached by transfusion) Glutamate pyruvate transaminase (GPT)/glutamate oxaloacetate transaminase (GOT) < 3 x upper limit of normal (ULN) (or < 5 x ULN in case of liver metastasis) Bilirubin < 3 x ULN (or < 5 x ULN in case of liver metastasis) Creatinine < 1.5 x ULN Females of child-bearing potential (FOCBP) and males must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 2 weeks following completion of therapy; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; likewise, if the female partner of a male patient becomes pregnant while participating in this study, he should inform his treating physician immediately; NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) Female patients must have a negative urine pregnancy test within 7 days prior to registration; if urine test is positive, it should be followed by serum pregnancy test Patients must sign an informed consent prior to registration and before undergoing any study-specific procedures indicating that they are aware of the investigational nature of this study Patient must have the ability to swallow and retain oral medication Patient must have the ability to comply with all study requirements Exclusion Criteria: Any uncontrolled neurological symptom attributed to CNS metastasis Brain metastasis must not be impending herniation or other significant vasogenic edema requiring increasing steroid doses; lesions must not have frank hemorrhage Patients with leptomeningeal disease are not eligible for participation Any significant medical illnesses or infection that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy are not eligible for participation Known human immunodeficiency virus (HIV) positive status Known active hepatitis B and/or C Previous treatment with palbociclib Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib are not eligible; AND/OR patients who have had prior exposure to compounds of similar chemical or biologic composition to palbociclib are not eligible hypersensitivity to any component of palbociclib are not eligible for participation Patients being treated with any other experimental agents/clinical trials are not eligible for participation; if the patient is on any investigational agent, a wash-out period of minimum 2 weeks prior to registration is mandatory for the patient to be eligible for the study Patients who are on any prohibited medication; a wash-out period of minimum 2 weeks prior to registration is mandatory for the patient to be eligible for the study Inability to swallow capsules, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of study drugs, major resection of the stomach or small bowel, or gastric bypass procedure Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible: Ongoing or active infection requiring systemic treatment Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia: except atrial fibrillation (AF) and supraventricular tachycardia (SVT) that are controlled by medication Psychiatric illness/social situations that would limit compliance with study requirements Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints Female patients who are pregnant or nursing are not eligible

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (palbociclib)<br>Patients receive palbociclib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with HER2 positive breast cancer may also receive trastuzumab IV over 30-90 minutes every 3 weeks. | Procedure: Cognitive Assessment<br>* Ancillary studies<br>Drug: Palbociclib<br>* Given PO<br>* Other names: PD-332991;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Biological: Trastuzumab<br>* Given IV<br>* Other names: Trastuzumab Biosimilar PF-05280014;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Response Rate (RRR) in the CNS in Patients With HER2-positive Breast Cancer Who Have Brain Metastasis Treated With Palbociclib | Assess the Radiographic Response Rate (RRR) in the CNS by modified Response Assessment in Neuro-Oncology Criteria Brain Metastasis (modifiedRANO-BM). Maximum response prior to disease progression will be used. In General: Complete Response : Disappearance of all lesions Partial Response: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression.) | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | Determine the safety and tolerability of palbociclib in patients with HER2-positive breast cancer by evaluating number, frequency, and severity of adverse events using Common Terminology Criteria for Adverse Events version 4.03. The number of patients that experienced SAEs that were determined to be at least possibly related to study drug are reported below. | Up to 3 years | 
| Overall Survival (OS) | Evaluate OS in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib. OS is defined as the time from treatment initiation until death due to any cause. Number of patients remaining alive as of the last follow up date, is reported below. | Up to 3 years | 
| Progression Free Survival (PFS) | Determine the PFS in patients with HER2-positive breast cancer who have brain metastasis treated with palbociclib where PFS is defined as the time from treatment initiation to documented disease progression or death for any reason. Below shows the number of patient who discontinued treatment due to progression of disease. | Up to 3 years | 
| Overall Response Rate (ORR) | Evaluate systemic ORR defined as partial response or complete response assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 where: Complete Response = complete disappearance of all lesions Partial Response = At least 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. | Up to 3 years | 
| Time to CNS Progression | Time to CNS progression will be defined as the time from treatment initiation to documented disease progression (modified RANO-BM criteria) in the CNS. | Up to 3 years |