Neoadjuvant Study of Two Platinum Regimens in Triple Negative Breast Cancer

Study Overview
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Brief Summary
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Evaluate if the two carboplatin containing chemotherapy regimens will reduce the growth of breast cancer cells in women with Stage I, II, or III triple negative breast cancer.

Detailed Description
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Sporadic and germline BRCA mutation associated triple-negative breast cancer share several pathological and molecular similarities which have led to the exploration of DNA damaging agents like platinum compounds in patients with triple-negative breast cancer. Recent studies demonstrate that addition of neoadjuvant carboplatin to doxorubicin/cyclophosphamide/taxane-based chemotherapy improves pathological complete response in patients with stage I-III triple-negative breast cancer but also increase toxicity. A recent study reported encouraging pathological complete response rates with a non-anthracycline carboplatin plus docetaxel neoadjuvant chemotherapy regimen in a cohort of 49 triple negative breast cancer patients. This chemotherapy regimen of carboplatin plus docetaxel yielded an overall pathological complete response rate of 65% in unselected triple-negative breast cancer with pathological complete response rates of 61% in sporadic and 77% in germline BRCA-associated triple-negative breast cancer. The chemotherapy regimen of carboplatin/docetaxel is well tolerated and should be studied further and compared with regimens that add carboplatin to the standard anthracycline/taxane containing regimens. This is the basis for the proposed randomized neoadjuvant phase II study to further estimate and compare pathological complete response rates of carboplatin plus docetaxel x 6 cycles to carboplatin plus paclitaxel x 4 cycles followed by doxorubicin plus cyclophosphamide x 4 cycles in stage I-III triple negative-breast cancer.

Official Title
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Randomized Open Label Phase II Trial of Neoadjuvant Carboplatin Plus Docetaxel or Carboplatin Plus Paclitaxel Followed by Doxorubicin Plus Cyclophosphamide in Stage I-III Triple-negative Breast Cancer

Conditions
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Triple-negative Breast Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly diagnosed stage I (T>1cm), II or III triple negative breast cancer who have not had definitive breast surgery or received systemic chemotherapy The invasive tumor must be hormone receptor-poor, defined as both estrogen receptor and progesterone receptor staining present in ≤ 10% of invasive cancer cells by Immunohistochemistry. HER- 2 negativity will be based on the current ASCO-CAP guidelines for HER testing No prior chemotherapy, endocrine therapy or radiation therapy with therapeutic intent for this cancer Female subjects age 18 - 70 years ECOG Performance Status of 0-1 Adequate organ and marrow function as defined below: Leukocytes ≥ 3,000/uL Absolute neutrophil count ≥ 1500/uL Platelets ≥ 100,000/uL Total bilirubin ≤ 1.5mg/dL AST(SGOT)/ALT(SPGT) ≤ 2 x institutional upper limit of normal Creatinine ≤ 1.5mg/dl and/or Creatinine Clearance ≥ 60mL/min Serum albumin ≥ 3.0 g/dL Women of child-bearing potential must agree to use adequate contraception Pretreatment lab values must be performed within 14 days of treatment initiation, and other baseline studies performed within 30 days prior to registration Subjects should have LVEF ≥ 50% by echocardiogram or MUGA scan performed within 4 weeks prior to treatment initiation Subjects should have breast and axillary imaging with breast MRI or breast and axillary ultrasound within 4 weeks prior to treatment initiation Subjects with clinically/radiologically abnormal axillary lymph nodes should have pathological confirmation of disease with image guided biopsy/fine needle aspiration. Subjects must be already enrolled in P.R.O.G.E.C.T observational registry Staging to rule out metastatic disease is recommended for subjects with clinical stage III disease Subjects with bilateral disease are eligible if they meet other eligibility criteria. Neuropathy: No baseline neuropathy grade > 2 Exclusion Criteria: Current or anticipated use of other investigational agents Subject has received chemotherapy, radiotherapy or surgery for the treatment of breast cancer Subject with metastatic disease History of allergic reactions to compounds of similar chemical or biologic composition to carboplatin, docetaxel, doxorubicin, cyclophosphamide, paclitaxel, or other agents used in the study Subjects with inflammatory breast cancer Uncontrolled intercurrent illness including, but not limited to ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements Subject is pregnant or nursing Subjects with concomitant or previous malignancies within the last 5 years. Exceptions include: adequately treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, and ductal carcinoma in situ (DCIS). Ejection Fraction <50% on ECHO or MUGA Cardiac function: Subjects with congestive heart failure, myocardial infarction, unstable angina pectoris, an arterial thrombotic event, stroke or transient ischemia attack within the past 12 months, uncontrolled hypertension (Systolic BP>160 or Diastolic BP>90), uncontrolled or symptomatic arrhythmia, or grade ≥ 2 peripheral vascular disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Active Comparator: Carboplatin + Paclitaxel then Doxorubicin + Cyclophosphamide<br>Paclitaxel (80mg/m2) given IV every week x12 weeks and Carboplatin (AUC 6) given IV every 21 days x 4 cycles, followed by Doxorubicin (60mg/m2) given IV and Cyclophosphamide (600mg/m2) given IV every 14 days X 4 cycles | Drug: Paclitaxel<br> <br> * Other names: taxol;Drug: Carboplatin<br> <br> * Other names: paraplatin;Drug: Doxorubicin<br> <br> * Other names: adriamycin;Drug: Cyclophosphamide<br> <br> * Other names: cytoxin, procytox;|
| Active Comparator: Carboplatin + Docetaxel<br>Carboplatin (AUC 6) given IV and Docetaxel (75mg/m2) given IV every 21 days x 6 cycles | Drug: Carboplatin<br> <br> * Other names: paraplatin;Drug: Docetaxel<br> <br> * Other names: taxotere;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pathological Complete Response | To evaluate the pathological complete response rates with neoadjuvant chemotherapy regimens of carboplatin plus paclitaxel x 4 cycles followed by doxorubicin plus cyclophosphamide X 4 cycles and carboplatin plus docetaxel X 6 cycles in subjects with stage I-III triple-negative breast cancer. Pathological complete response is defined as no evidence of disease in the breast and axilla at the time of pathology review except for DCIS. | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Minimal Residual Disease | To evaluate minimal residual disease rates (residual cancer burden 0+1) with two neoadjuvant chemotherapy regimens in subjects with stage I-III triple-negative breast cancer. | 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TNBC, breast cancer, neoadjuvant, carboplatin, docetaxel, paclitaxel, doxorubicin, cyclophosphamide