Preoperative Palbociclib in Patients With DCIS of the Breast That Are Candidates for Surgery

Study Overview
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Brief Summary
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This is a feasibility study which will evaluate the effects of pre-operative treatment of DCIS of the breast with palbociclib. Patients with biopsy-proven DCIS are eligible for the study. There will be 2 independent and unrelated study groups of 12 patients each, for a total of 24 patients: Group A, of male or female patients treated with palbociclib single agent (n=12); Group B, untreated, of male or female patients who consented translational studies in blood, as well as diagnostic and definitive surgical specimen, but not the pre-operative treatment with palbociclib (n=12).

Official Title
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Preoperative Palbociclib in Patients With DCIS of the Breast That Are Candidates for Surgery

Conditions
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DCIS

Intervention / Treatment
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* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for all patients (Groups A and B): Signed informed consent obtained prior to any study specific assessments and procedures Age ≥18 years Premenopausal and postmenopausal women, or men Current pathologic diagnosis of DCIS of the breast of any receptor status; History of previous DCIS allowed provided that the patient is currently off systemic risk-reduction endocrine therapy; History of previous invasive breast cancer adequately treated and that is currently in remission and unrelated to current DCIS (based on primary tumor location) is allowed as long as patient is currently off systemic therapy for that invasive cancer for at least 4 weeks prior to pre-treatment biopsy (diagnostic biopsy); Patients with multifocal or multicentric lesions are allowed, as long as at least one lesion is histologically confirmed DCIS and overall clinical AJCC Stage 0 or I. A formalin-fixed paraffin-embedded (FFPE) tumor tissue block from diagnostic biopsy must be transmitted to MedStar Georgetown University Hospital Pathology Department repository and confirmation of receipt must be available prior to enrollment. Positive Rb by immunohistochemistry in the DCIS component of the lesion - must be performed at CLIA-approved setting (for instance, MGUH); Rb staining will be considered positive when 1+ or above (in a scale of 0, 1+, 2+ or 3+) In the absence of histologic diagnosis of DCIS, patient may undergo fresh biopsy for eligibility, provided: this invasive procedure is not a Fine Needle Aspiration (FNA); AND this procedure is a core biopsy, stereotactic biopsy or incisional biopsy of the suspicious breast lesion; AND the primary lesion is not completely resected during the procedure. The patient is candidate for and is willing to receive definitive surgical therapy for DCIS ECOG performance status 0-1 Willingness to provide a sample of tissue collected at definitive surgery for research Inclusion criteria specific to treatment Group A: Patients must be able and willing to swallow and retain oral medication Absolute neutrophil count (ANC) ≥ 1,500/mm3 Platelets ≥ 120,000/mm3 Hemoglobin ≥ 10g/dL Total serum bilirubin ≤ ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with documented Gilbert's Syndrome. Aspartate amino transferase (AST or SGOT) and alanine amino transferase (ALT or SGPT) ≤ 1.5 × institutional ULN Serum creatinine within normal institutional limits or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN. Pregnancy must be ruled out: serum or urine pregnancy test must be negative within 14 days of treatment start in women of childbearing potential. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before enrollment, or who have undergone tubal ligation, bilateral oophorectomy, total hysterectomy. Willingness to undergo adequate contraception if childbearing potential; women of childbearing potential and male patients randomized into treatment Group A must use adequate contraception for the duration of protocol treatment and for 3 months after the last treatment with palbociclib if they are in Group A; adequate contraception is defined as one highly effective form (i.e. abstinence, (fe)male sterilization) OR two effective forms (e.g. non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository). Exclusion Criteria for all patients (Groups A and B): Concurrent therapy with other Investigational Products Invasive carcinoma present in the diagnostic biopsy, microinvasion is allowed Uncontrolled intercurrent illness including (active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, pulmonary embolism in the past 6 months, or psychiatric illness/social situations that would limit compliance with study requirements). Unable to comply with study requirements Hormone therapies containing estrogen, progesterone, GnRH agonists and antagonists within 4 weeks from diagnostic biopsy. Therapy with any CDK inhibitor in the past 3 months Exclusion criteria specific to treatment Group A: History of allergic reactions attributed to compounds of chemical or biologic composition similar to palbociclib Presence of a condition that would interfere with enteric absorption of palbociclib Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 7 days prior to enrollment; breastfeeding must be discontinued prior to study entry (Group A only). Patients on combination antiretroviral therapy, i.e. those who are HIV+ (potential for pharmacokinetic interactions or increased immunosuppression with palbociclib). Patients receiving any medications or substances that are potent inhibitors or inducers of CYP3A isoenzymes within 7 days of enrollment or during participation on study Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis, etc.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Patients enrolled to Group A will receive a 12-day course of Palbociclib before surgery. They will receive Palbociclib 100mg PO daily x 12 days. | Drug: Palbociclib<br>* Palbociclib capsules for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase inhibitor.<br>* Other names: Ibrance;|
| No Intervention: Group B<br>These patients will receive no pre-operative treatment. Core biopsies from diagnosis and material from definitive surgery will be collected for translational studies and tissue banking. They will also provide blood samples at screening and prior to definitive surgery. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility: recruitment rates | The approach will be considered feasible if more than 50% of the enrolled patients are treated and followed within protocol rules, if collected samples are suitable for studies, and if pathologic changes are detectable when comparing diagnostic and surgical specimens, or treated and untreated specimens. In Group A, patients will be treated with palbociclib alone, providing the opportunity to address if proposing this kind of treatment for these patients is feasible. Obtaining human data and feasibility data would be key for designing efficacy/definitive studies of palbociclib in DCIS. This will be measured through data collected on eCRFs regarding timeline from consent to treatment, and treatment to surgery, including treatment delivery (beginning date, end date, number of tablets taken) and date of definitive surgery, as well as number of drop outs. | 14 - 40 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathology: descriptive findings on H&E | Pharmacodynamic effects as measured by changes in tissue morphology (evaluated by H&E) in pre- and post-dose tumor specimens | 14 - 40 Days | 
| Pathology: descriptive findings on IHC | Pharmacodynamic effects as measured by changes in biomarkers Cdk4, Cdk6, pRb, Cyclin D1, Cyclin E (evaluated by IHC) in pre- and post-dose tumor specimens. | 14 - 40 Days | 
| Toxicity based on CTCAE | Will be evaluated by CTCAE. There is no plan to compare Groups A and B regarding efficacy or toxicity. Toxicity will be descriptive for each treatment group, independently. | 14 - 40 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, DCIS, Ductal Carcinoma In Situ, Palbociclib