Palbociclib and Endocrine Therapy for LObular Breast Cancer Preoperative Study (PELOPS)

Study Overview
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Brief Summary
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This research study is evaluating how well Breast Cancer responds to preoperative treatment with Endocrine treatment in combination with a drug called Palbociclib or Endocrine treatment alone as possible treatments for Hormone Receptor Positive Breast Cancer.

Detailed Description
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This is an open label phase II neoadjuvant clinical trial of Palbociclib in combination with endocrine therapy for hormone receptor positive early-stage breast cancer. The planned sample size is 180 participants. The study includes a window treatment phase followed by a treatment phase. In the window phase, participants will be treated with a two-week course of tamoxifen (Arm A) or letrozole (Arm B). In the treatment phase participants will be randomized to receive endocrine therapy in combination with palbociclib (Arm C) or endocrine therapy alone (Arm D) for a total duration of 24 weeks. Premenopausal patients with either invasive lobular or ductal carcinoma will be eligible to enroll directly into the treatment phase of the study. The study has two co-primary objectives: 1) 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 hormone receptor positive breast cancer for patients with invasive lobular and ductal carcinoma. 2) To evaluate the pathologic complete response (pCR) of endocrine therapy plus palbociclib and of endocrine therapy alone in breast cancer patients diagnosed with hormone receptor positive invasive breast cancer.

Official Title
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Palbociclib and Endocrine Therapy for LObular Breast Cancer Preoperative Study (PELOPS): A Randomized Phase II Study of Palbociclib With Letrozole Versus Letrozole Alone for Invasive Lobular Carcinoma and Invasive Ductal Carcinoma

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Letrozole
* Drug: Tamoxifen
* Drug: Palbociclib
* Drug: Endocrine Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 PR), HER2 negative, invasive breast cancer. ER, PR and HER2 measurements should be performed according to institutional guidelines, in a CLIA-approved setting in the 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. For the treatment phase: Patients with any histological subtype are eligible. Women 18 years of age. Men are not eligible. ECOG performance status 0 or 1 Required laboratory values: Absolute neutrophil count ≥ 1,500/mm3 Platelets ≥ 100,000/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) ≤ 2.0 × institutional ULN Serum creatinine within normal institutional limits or creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN Postmenopausal patients defined as no spontaneous menses ≥1 year (12 months) or post bilateral surgical oophorectomy. Premenopausal patients are eligible to participate provided they are considered in chemical menopause. Premenopausal patients should receive ongoing treatment with LHRH agonists (goserolin 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 SLN procedure will be performed to determine the presence of metastatic disease in the lymph nodes. Patients with multifocal or multicentric 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 IUD and condom/occlusive cap with spermicidal foam / gel / film / cream/ suppository). Hormonal contraceptive methods are not allowed. Patients with a history of ipsilateral or contralateral 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. Exclusion Criteria: Concurrent therapy with other Investigational Products. Prior therapy with any 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, CT, MRI, and/or 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 CYP3A isoenzymes within 7 days of randomization 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 any malignancy are ineligible except for the following circumstances: 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 HIV-positive, are ineligible because of the potential for pharmacokinetic interactions or increased immunosuppression with palbociclib. 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 AI.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A Tamoxifen followed by Endocrine Therapy<br>Tamoxifen is given in the Window of Treatment phase for 2 weeks followed by Endocrine Therapy for 24 weeks. | Drug: Tamoxifen<br> <br> * Other names: Soltanox;Drug: Endocrine Therapy<br> <br> * Other names: Nolvadex;|
| Experimental: Arm B Letrozole Followed By Endocrine Therapy<br>Letrozole is given in the Window of Treatment phase for 2 weeks followed by Endocrine Therapy for 24 weeks. | Drug: Letrozole<br> <br> * Other names: Femara;Drug: Endocrine Therapy<br> <br> * Other names: Nolvadex;|
| Experimental: Tamoxifen Followed By Endocrine Therapy and Palbociclib<br>Tamoxifen is given in the Window of Treatment phase for 2 weeks followed by Endocrine Therapy in combination with Palbociclib for 24 weeks. | Drug: Tamoxifen<br> <br> * Other names: Soltanox;Drug: Palbociclib<br> <br> * Other names: Ibrance;Drug: Endocrine Therapy<br> <br> * Other names: Nolvadex;|
| Experimental: Letrozole Followed By Endocrine Therapy and Palbociclib<br>Letrozole is given in the Window of Treatment phase for 2 weeks followed by Endocrine Therapy in combination with Palbociclib for 24 weeks. | Drug: Letrozole<br> <br> * Other names: Femara;Drug: Palbociclib<br> <br> * Other names: Ibrance;Drug: Endocrine Therapy<br> <br> * Other names: Nolvadex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Anti-proliferative Activity of Patients Given Letrozole Versus Tamoxifen During the Window Phase | Log fold change in anti-proliferative activity of Letrozole versus Tamoxifen within cohorts of hormone receptor positive breast cancer for patients with invasive lobular and ductal carcinoma during the window phase. Higher absolute value indicates larger change in the anti-proliferative activity | baseline to day 15 | 
| Pathologic Complete Response (pCR) of Patients Given Endocrine Therapy Plus Palbociclib and of Endocrine Therapy Alone During the Treatment Phase | Residual Cancer Burden index (RCB) between hormone receptor positive invasive breast cancer patients given endocrine therapy plus palbociclib (Arm C) and endocrine therapy alone (Arm D). RCB score is used to assess the response to neoadjuvant chemotherapy in breast cancer patients and is in a scale of 0 to infinity. Higher RCB score indicates more tumor burden remaining, thus worse outcome. | day 15 to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Odds Ratio of Achieving Cell Cycle Arrest at the End of Window Phase | Odds Ratio of Achieving Cell Cycle Arrest at the end of Window Phase in hormone receptor positive invasive breast cancer patients given Tamoxifen vs Letrozole. Cell cycle arrest is defined to be percentage of Ki67<2.7 | baseline to day 15 | 
| Change in RCB Index Between Arm C and Arm D During the Treatment Phase | The estimate of RCB index change for patients who receive both endocrine and Palbociclib instead of endocrine alone, but have the same lymph node status, tumor size and menopausal status. RCB score is used to assess the response to neoadjuvant chemotherapy in breast cancer patients and is in a scale of 0 to infinity. Higher RCB score indicates more tumor burden remaining, thus worse outcome. | day 15 to 24 weeks | 
| Number of Participants With RCB Response in Arm C and Arm D During the Treatment Phase | RCB response is defined as RCB-0 or RCB-I; RCB not response is defined as RCB-II or RCB-III Residual Cancer Burden (RCB) considers residual disease in the tumor bed and lymph nodes after NAC, generating a continuous score which is then grouped into four categories: RCB-0, RCB-I, RCB-II and RCB-III. Higher RCB group reflects more tumor burden remaining, thus worse outcome | day 15 to 24 weeks | 
| Percentage of Participants With Clinical Response in Arm C and Arm D in the Treatment Phase | Percentage of Participants with Clinical Response in Arm C and Arm D in Breast cancer patients diagnosed with hormone receptor positive invasive breast cancer; Clinical response rate is defined as the number of partial and complete responses after preoperative endocrine therapy plus palbociclib (Arm C) and of endocrine therapy alone (Arm D) | day 15 to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Invasive Lobular Carcinoma