This research study is studying Ruxolitinib as possible treatment for Inflammatory Breast Cancer (IBC). The Following drugs will be use in combination with Ruxolinitinib. * Paclitaxel (also called Taxol) * Doxorubicin also called Adriamycin * Cyclophosphamide, also called Cytoxan
This is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (U.S. Food and Drug Administration) has not approved Ruxolitinib for Inflammatory Breast Cancer (IBC), but is has been approved for other uses. Ruxolitinib is a newly discovered drug that has been shown to block a pathway (called the IL6/JAK/Stat pathway) that may be important in cancer, including triple negative inflammatory breast cancer. Ruxolitinib brings proteins groups together, which can result in gene (DNA) changes. These DNA changes may stop cancer cells from growing. Paclitaxel (also called Taxol), Doxorubicin and Cyclophosphamide (also called Adriamycin and Cytoxan, ("AC")) are drugs FDA approved for breast cancer patients. They have been shown to result in death of cancer cells when given as preoperative treatment of women with inflammatory breast cancer (IBC). Laboratory studies have shown that Ruxolitinib may make Paclitaxel more effective. In this research study, the investigators are evaluating Ruxolitinib in combination with Paclitaxel followed by the standard chemotherapy, AC. Researchers will also evaluate how the IL6/JAK/Stat pathway is affected by this combination of drugs by studying biopsies and surgical specimens.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
23
15 or 20 mg, twice daily by mouth. The run-in part of ruxolitinib lasts 7 days; The treatment of ruxolitinib part lasts 12 weeks.
80 mg/m2, IV (in the vein) weekly for 12 weeks.
60 mg/m2, IV (in the vein) every 14 days for 4 doses.
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Mayo Clinic
Rochester, Minnesota, United States
Duke University Medical Center
Durham, North Carolina, United States
MD Anderson Cancer Center
Houston, Texas, United States
Biologic Response To 7-Day Run-In Window Phase Treatment of Ruxolitinib Alone or Ruxolitinib Plus Paclitaxel
Biologic response to 7-day run-in phase treatment, defined as a change in phosphorylated STAT3 (pSTAT3) expression from moderate/high positive (pSTAT3-positive) in pre-run-in phase sample to negative or weakly positive/equivocal (pSTAT3-negative) in post-run-in samples. pSTAT3 status was determined by evaluating the percent positive cells and the strength of staining (weak vs. strong/moderate) in relation to positive and negative controls. A T-score was calculated based on percent-stained cells and intensity of staining and interpreted as follows: Scores 0-4 are negative/weakly positive (pStat3 negative) and 5-8 are moderate/high positive (pStat3 positive). Hence, pStat3 negative indicates a biologic response or a decrease in pSTAT3 levels.
Time frame: 7 days
Pathologic Complete Response Rate (pCR) After Preoperative Therapy
Pathologic Complete Response rate (pCR) is defined as the absence of invasive carcinoma within the breast and axillary lymph nodes following preoperative therapy.
Time frame: 28 weeks
Assess Change in STAT3 Gene Expression Following run-in Treatment
Change of STAT3 gene expression between pretreatment and post-ruxolitinib run-in (after 7 days of ruxolitinib alone or with one dose of weekly paclitaxel) biopsy specimens. RNA-seq was performed on a subset of tumor pairs (n=4 per run-in treatment group). Enrichment analysis for JAK-STAT and IL-6 Hallmark signatures obtained a Gene Set Variation Analysis (GSVA) enrichment score as a measure of STAT3 gene expression. The GSVA enrichment score is a continuous unitless measure that summarizes joint expression of multiple genes into a single value. A positive value indicates greater, and a negative value a lesser, enrichment of pathway signatures; thus a negative pre- to post-runin change in the value indicates a decrease in the STAT3 expression after the treatment, and a positive values indicates increase in STAT3 expression after treatment.
Time frame: 7 Days
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600 mg/m2, IV (in the vein) every 14 days for 4 doses.
Determine Efficacy Defined as Disease-Free Survival (DFS)
Disease-Free Survival (DFS) is defined as time of surgery, among the subset of patients who underwent surgery (n=21), until occurrence of recurrence, contralateral cancer, death attributable to any cause, second primary cancer other than breast. DFS was censored at date of last assessment.
Time frame: 2 years
Determine Efficacy Defined as Time to Treatment Failure (TTF)
The endpoint is now more commonly known as event-free survival (EFS). Defined as time of treatment initiation until occurrence of recurrence, contralateral cancer, death attributable to any cause, second primary cancer other than breast or occurrence of progressive disease during preoperative therapy or treatment of disease that is not surgically resectable; otherwise censored at last disease follow-up.
Time frame: 2 years
Determine Efficacy Defined as Overall Survival (OS)
Overall survival (OS) is defined as time from surgery until death from any cause or from treatment initiation until death from any cause.
Time frame: 2 years
Assess Residual Cancer Burden (RCB) Differences After Preoperative Therapy
Residual cancer burden (RCB) is a continuous variable (RCB0 through RCB-IV) derived from the primary tumor dimensions, cellularity of the tumor bed, and axillary nodal burden as described in Symmans et al, 2007; where RCB-0 equals pathologic complete response (pCR) and considered the best prognosis and RCB-IV is considered the worst prognosis.
Time frame: 28 weeks
Changes in Interleukin 6 (IL-6) Plasma Levels During Treatment
Elevations in interleukin (IL-6) and C-reactive protein (CRP) have been associated with worse clinical outcomes in patients with breast cancer. To determine whether STAT3 pathways were changed in the treatment groups, enrichment of JAKSTAT3 or IL-6 pathway-related gene signatures in the post-window phase samples compared to pre-window phase samples was analyzed. Enrichment analysis for JAK-STAT and IL-6 hallmark signatures were calculated using gene set variation analysis (GSVA) package. Each hospital followed their institutional guidelines for CRP and IL-6 measurements.
Time frame: 28 weeks
Changes in C-reactive Protein (CRP) Plasma Levels During Treatment
Systemic biologic responses to ruxolitinib were assessed using serum IL-6 and c-reactive protein (CRP) levels. CRP levels are associated with poor prognosis and increased inflammatory response. Therefore, CRP levels in combination with pSTAT3 staining, could potentially be used as a more reliable method to select patients who would benefit from ruxolitinib treatment. To further analyze the effect of ruxolitinib throughout treatment, serum for CRP assessment was collected from patients at pre-window phase, post-window-phase, following 12-week neoadjuvant paclitaxel with or without ruxolitinib and immediately before surgery (pre-surgery). Each hospital followed their institutional guidelines for CRP measurements.
Time frame: 28 weeks