Neoadjuvant Study of Palbociclib in Combination With Letrozole and Trastuzumab in Stage II-III ER+ HER2+ Breast Cancer

Study Overview
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Brief Summary
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The investigators propose to influence estrogen receptor (ER) signaling by combining endocrine therapy with CDK4/6 inhibition along with trastuzumab in ER+/ human epidermal growth factor receptor 2 (HER2)+ early stage breast cancer.

Official Title
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A Phase II Neoadjuvant Study of Palbociclib in Combination With Letrozole and Trastuzumab as Neoadjuvant Treatment of Stage II-III ER+ HER2+ Breast Cancer (PALTAN)

Conditions
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Breast Cancer, Cancer of Breast, Breast Carcinoma

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Letrozole
* Biological: Trastuzumab
* Drug: Goserelin
* Procedure: Breast surgery
* Procedure: Research tumor biopsy
* Procedure: Research bone marrow (OPTIONAL)
* Procedure: Research blood sample
* Genetic: Research blood for germline DNA
* Procedure: Blood for detection of circulating tumor cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed clinical stage II or III ER+/HER2+ breast cancer with complete surgical excision of the breast cancer after neoadjuvant therapy as the treatment goal, staging criteria is to be based on AJCC 7. Tumor size at least 2 cm in one dimension by clinical or radiographic exam (World Health Organization (WHO) criteria). Patients with histologically confirmed palpable lymph nodes may be enrolled regardless of breast tumor size. A palpable mass is not required as long as the mass is at least 2 cm in one dimension by radiographic exam. At least 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 Normal bone marrow and organ function as defined below: Leukocytes ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcl Platelets ≥ 100,000/mcl Total bilirubin ≤ institutional upper limit of normal (IULN) AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Left ventricular ejection fraction (LVEF) ≥ 50% by transthoracic echocardiogram or multigated acquisition scan (MUGA) Baseline corrected QT interval (QTcF) < 480 ms Women of childbearing potential must agree to undergo pregnancy testing within 14 days of study entry and agree to use adequate contraception (barrier method of birth control, abstinence, not hormonal) prior to study entry and for the duration of study participation as well as chemical LHRH Agonist with goserelin. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Prior systemic therapy for indexed breast cancer. Indeterminate or negative HER2 status. Inflammatory breast cancer. A history of other malignancy ≤ 5 years from diagnosis of indexed BC with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix. Currently receiving any other investigational agents or received any within the past 28 days. Know to be HIV positive. Known hepatitis B or C infection. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib, letrozole, trastuzumab, any other aromatase inhibitor, any other monoclonal antibody, or other agents used in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia. Current use or anticipated need for food or drugs that are known strong CYP3A4 inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone, diltiazem, and delavirdine) or inducers (i.e. dexamethasone, glucocorticoids, progesterone, rifampin, phenobarbital, St. John's wort). Any condition that impairs the ability to swallow or absorb oral medication (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affective absorption). Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.

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: Palbociclib + letrozole + trastuzumab +/- goserelin<br>Neoadjuvant palbociclib + letrozole (plus goserelin if premenopausal) + trastuzumab for a total of 16 weeks, consisting of (4) 28-day cycles Definitive surgery will be performed preferably within 6 weeks after the end of Cycle 4. Letrozole and trastuzumab will continue until the day of surgery. Letrozole will continue to be taken daily and trastuzumab will be given every 3 weeks per standard of care guidelines. Adjuvant therapy following definitive surgery will be at the discretion of the treating physician | Drug: Palbociclib<br>* Palbociclib is an oral drug given at a dose of 125 mg daily on Days 1-21 of each 28-day cycle for a total of 4 cycles.<br>* Other names: Ibrance;Drug: Letrozole<br>* Letrozole is an oral drug given at a dose of 2.5 mg orally once a day. It will be taken continuously (Days 1-28 of each cycle) until the day of definitive surgery.<br>* Other names: Femara®;Biological: Trastuzumab<br>* Or FDA approved biosimilar Trastuzumab will be administered on a weekly basis for 16 weeks (on Days 1, 8, 15, and 22 of each 28-day cycle for a total of 4 cycles). The first dose of trastuzumab on Cycle 1 Day 1 will be a loading dose of 4 mg/kg IVPB over 90 minutes. Subsequent doses of trastuzumab will be 2 mg/kg IVPB over 30 minutes. Weekly trastuzumab will continue after the completion of Cycle 4 of palbociclib until surgery.<br>* Other names: Herceptin®;Drug: Goserelin<br>* Goserelin is given subcutaneously at a dose of 3.6 mg on Day 1 of each cycle. Goserelin will be continued (once every 28-days) after the completion of Cycle 4 of palbociclib if required.<br>* Other names: Zoladex;Procedure: Breast surgery<br>* Standard of care<br>Procedure: Research tumor biopsy<br>* Baseline, cycle 1 day 15, and surgery<br>Procedure: Research bone marrow (OPTIONAL)<br>* Baseline and surgery<br>Procedure: Research blood sample<br>* Baseline, cycle 1 day 15, surgery, and yearly post-surgery for 5 years<br>Genetic: Research blood for germline DNA<br>* Baseline<br>Procedure: Blood for detection of circulating tumor cells<br>* Baseline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pathologic Complete Response (pCR) | A pathologic complete response (pCR) is defined as no histology evidence of invasive tumor cells in the surgical breast specimen and sentinel or axillary lymph nodes. | Completion of 4 cycles of treatment (approximately 16 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Palbociclib in Combination With Neoadjuvant Letrozole and Trastuzumab (or FDA Approved Biosimilar) as Measured by Number of Participants With Grade 3 & 4 Adverse Events | -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. | 30 days after completion of neoadjuvant therapy (approximately 21 weeks) | 
| Change in Patient Reported Outcomes as Measured by NCI PRO-CTCAE | Answers ranging from None to Very Severe (none=0 to very severe=4); Not at All to Very Much (not at all=0 to very much=4), Never to Almost Constantly (0=never to almost constantly=4) PRO-CTCAE responses are scored from 0 to 4, and there are no standardized scoring rules yet established for how to combine attributes into a single score or how best to analyze PRO-CTCAE data longitudinally. PRO-CTCAE scores for each attribute (frequency, severity and/or interference) will be presented descriptively | Baseline, cycle 2 day 1 (approximately 29 days), and end of cycle 4 (approximately 16 weeks) |