Carboplatin and Nab-Paclitaxel With or Without Vorinostat in Treating Women With Newly Diagnosed Operable Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as carboplatin and paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vorinostat may also help carboplatin and paclitaxel albumin-stabilized nanoparticle formulation work better by making tumor cells more sensitive to the drugs. Giving chemotherapy with or without vorinostat before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This randomized phase II trial is studying how well giving carboplatin together with paclitaxel albumin-stabilized nanoparticle formulation works with or without vorinostat in treating women with breast cancer that can be removed by surgery.

Detailed Description
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OBJECTIVES: Primary To determine pathological complete response (pCR) rates in patients with HER2-negative primary operable breast cancer treated with neoadjuvant therapy comprising carboplatin and paclitaxel albumin-stabilized nanoparticle formulation (CP) with vs without vorinostat. Secondary To evaluate the safety of these regimens in these patients. To estimate clinical complete response (cCR) rates in patients treated with these regimens. To correlate baseline and change (day 15) in surrogate uptake values (SUV) on FDG-PET with pathological and clinical response in patients treated with these regimens, and to determine what percent of women with ≥ 25% or ≥ 50% reduction in SUV on day 15 achieve a pCR and a cCR to CP with vs without vorinostat. To correlate baseline and change in markers of proliferation with pathological and clinical response in patients treated with these regimens. To evaluate long term outcomes (e.g., recurrence of the breast cancer, development of a new cancer, or death) for patients treated with these regimens. Tertiary To evaluate baseline and change in candidate gene methylation and expression profiles. To evaluate baseline and change in tissue and peripheral blood mononuclear cell histone acetylation. To compare cCR and pCR in women with basal-like features versus other subtypes. OUTLINE: This is a multicenter, randomized, double-blind, phase II study (primary study portion) with a 6-12 patient run-in portion. Run-in portion: Patients receive carboplatin IV and paclitaxel albumin-stabilized nanoparticle formulation IV on day 1 and oral vorinostat on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Once safety of the combination of chemotherapy and vorinostat is confirmed, subsequently enrolled patients are entered to the primary study portion. Primary study portion: Patients are stratified by hormone receptor status (estrogen receptor [ER]-negative and progesterone receptor [PR]-negative vs ER-positive and/or PR-positive). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive carboplatin IV and paclitaxel albumin-stabilized nanoparticle formulation IV on day 1 and an oral placebo on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive carboplatin and paclitaxel albumin-stabilized nanoparticle formulation as in arm I and oral vorinostat on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after completion of neoadjuvant chemotherapy, patients undergo breast conserving surgery or mastectomy at the discretion of the treating physician. Patients undergo tumor tissue biopsy at baseline, day 15, and at the time of definitive surgery. Samples are analyzed by immunohistochemistry (IHC), RNA extraction, and gene expression analysis using RT-PCR to identify candidate markers for response and molecular profiles that may be relevant to an understanding of drug mechanisms. Methylation of relevant genes (e.g., ERalpha, APC-1, RARbeta, cyclin D2, Twist, RASSF1A, and HIN-1) are evaluated by quantitative multiplex methylation-specific PCR. Changes in gene expression as a result of treatment are determined by IHC or quantitative RT-PCR. Blood samples are collected at baseline, day 15, at the time of definitive surgery, and 4 weeks after surgery for DNA methylation studies, pharmacogenomic studies, and histone acetylation assays. Patients also undergo fludeoxyglucose F 18-positron emission tomography (FDG-PET) or PET/CT at baseline and day 15 to assess treatment response as measured by standardized uptake values. After completion of study treatment, patients are followed every 6 months.

Official Title
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A Multi-Institutional Double-Blind Phase II Study Evaluating Response and Surrogate Biomarkers to Carboplatin and Nab-Paclitaxel (CP) With or Without Vorinostat as Preoperative Chemotherapy in HER2-negative Primary Operable Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: carboplatin
* Drug: paclitaxel albumin-stabilized nanoparticle formulation
* Drug: vorinostat
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed infiltrating ductal breast cancer by core needle biopsy Mixed ductal and lobular disease allowed Infiltrating lobular cancer allowed in the run-in portion only Unresected, clinically measurable disease, meeting 1 of the following clinical staging criteria: T2, T3, or T4 lesion, any N, M0 T1c, N1-3,M0 Patients with skin metastases to the ipsilateral breast for whom chemotherapy is planned prior to definitive surgery are eligible for the primary study portion HER2-negative disease Hormone receptor status* meeting 1 of the following criteria: Estrogen receptor (ER)-negative and progesterone receptor (PR)-negative ER-positive (grade II or III) and PR-positive or PR-negative NOTE: *Any ER or PR status for the run-in portion PATIENT CHARACTERISTICS: ECOG performance status 0-1 Menopausal status not specified ANC ≥ 1,500/mm³ Platelet count ≥ 150,000/mm³ Hemoglobin ≥ 9 g/dL Creatinine ≤ 1.5 times the upper limit of normal (ULN) Creatinine clearance ≥ 50 mL/min Total bilirubin normal AST(SGOT) and ALT(SGPT) ≤ 2.5 times (ULN) alkaline phosphatase ≤ 2.5 times ULN PT such that INR ≤ 1.5 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and PTT ≤ ULN Adequate cardiac function defined as no evidence of PR prolongation or AV block on baseline electrocardiogram (ECG) Willing to use effective, non-hormonal contraception while on treatment and for at least 3 months thereafter Not pregnant or nursing No pre-existing peripheral neuropathy ≥ grade 2 No history of severe hypersensitivity reaction to any drug formulated with polysorbate 80 or to E. coli-derived products No history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat No medical condition which, in the opinion of the investigator, puts the patient at risk of potentially serious complications while on this therapy PRIOR CONCURRENT THERAPY: At least 4 weeks since prior valproic acid or other histone deacetylase inhibitor No prior chemotherapy, radiotherapy, or endocrine therapy for this cancer Prior tamoxifen or raloxifene or another agent for prevention of breast cancer allowed as long as the patient has discontinued the treatment ≥ 1 month prior to baseline study biopsy No systemic treatment for prior cancer within the past 5 years (primary study portion) No prior or ongoing systemic treatment for this cancer (primary study portion) No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent histone deacetylase inhibitor No other concurrent chemotherapy, antiestrogen therapy, radiotherapy, or other investigational systemic therapy No other concurrent biologic therapy No other concurrent investigational drugs

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>Patients receive carboplatin IV and paclitaxel albumin-stabilized nanoparticle formulation IV on day 1 and an oral placebo on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. | Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: paclitaxel albumin-stabilized nanoparticle formulation<br>* Given IV<br>* Other names: Abraxane, nab-Paclitaxel;Other: placebo<br>* Given orally<br>|
| Experimental: Arm II<br>Patients receive carboplatin and paclitaxel albumin-stabilized nanoparticle formulation as in arm I and oral vorinostat on days 1-3. Treatment repeats weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. | Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: paclitaxel albumin-stabilized nanoparticle formulation<br>* Given IV<br>* Other names: Abraxane, nab-Paclitaxel;Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (pCR) Rate | The primary end point was pCR, defined as no viable invasive cancer in breast and axilla. All other cases were defined as non-pCR. The pCR rate was determined in each arm separately by performing an intent-to-treat (ITT) analysis of all randomized patients. Patients with unknown pCR status were considered non-responders. Computation of associated 90% confidence intervals did not account for the sequential design. | Time of breast cancer surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Measured by Number of Participants Who Experience Adverse Events | Number of participants who experience adverse events as defined by NCI CTCAE version 3.0 | up to 30 days post-treatment | 
| Number of Participants With Clinical Complete Response (cCR) | cCR in the breast on physical is defined as the absence of any palpable abnormality on breast exam Iie: no skin or breast thickening, mass or associated skin or nipple changes) | 12 weeks | 
| Change in Standard Uptake Value (SULmax) From Baseline to Day 15 on FDG-PET | Change in standard uptake value (SULmax) as measured by percentage reduction of SULmax. The standard uptake value used for the PET analysis was SULmax, which is the standard uptake value normalized for lean body mass. | Baseline and day 15 | 
| Absolute Change From Baseline in Ki-67 |  | Change from baseline to Cycle 1-Day 15 | 
| Change in Cumulative Methylation Index (CMI) | Change of CMI from baseline to Day 15 (D15), defined as log(D15 CMI + 1/baseline CMI + 1). The CMI was calculated as a sum of all gene-specific methylation indexes within a panel of 10 genes which included: HIST1H3C, AKR1B1, GPX7, HOXB4, TMEFF2, RASGRF2, COL6A2, ARHGEF7, TM6SF1, and RASSF1A. | Change from baseline to Day 15 | 
| Cumulative Methylation Index (CMI) at Day 15 |  | Day 15 | 
| Number of Participants Who Experience Death During Treatment |  | Up to 12 weeks | 
| Number of Participants Who Develop New Cancer |  | Up to death of last participant (duration unknown) | 
| Number of Participants With Recurrence of Breast Cancer |  | Up to death of last participant (duration unknown) | 
| Overall Survival |  | Up to death of last participant (duration unknown) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, ductal breast carcinoma, lobular breast carcinoma