Study Of Ruxolitinib (INCB018424) With Preoperative Chemotherapy For Triple Negative Inflammatory Breast Cancer

Phase II Study Of Combination Ruxolitinib (INCB018424) With Preoperative Chemotherapy For Triple Negative Inflammatory Breast Cancer

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

Study Overview

• Status: Active, not recruiting
• Conditions: Inflammatory Breast Cancer (IBC)
• Intervention / Treatment: Drug: Ruxolitinib; Drug: Paclitaxel; Drug: Doxorubicin; Drug: Cyclophosphamide

Detailed Description

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
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants must have histologically confirmed invasive breast cancer. All histologic subtypes are eligible.

• Patients must have known ER, PR, and HER2 status defined as triple-negative breast cancer (TNBC), defined as:

  --ER and PR <10% by immunohistochemistry, and HER2-negative ( as per ASCO/CAP guidelines, defined as IHC 0 or 1+, or FISH ratio <2.0 or HER2 copy number <6.0).

• Patients must have the clinical diagnosis of inflammatory breast cancer, involving an intact breast.
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of ruxolitinib in participants <18 years of age, children are excluded from this study.
• ECOG performance status 0 or 1.

• Participants must have normal organ and marrow function as defined below:

  • Leukocytes ≥ 3,000/mm3
  • Absolute neutrophil count ≥ 1,500/mm3
  • Platelets ≥ 100,000/mm3
  • Bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
  • AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal
  • Creatinine ≤1.5 x institutional upper limit of normal OR creatinine clearance > 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal
• Patients with evidence of extensive nodal involvement are allowed. Extensive nodal involvement is defined as metastatic disease involving any nodal region outside of the involved breast.
• Patients with minimal metastatic disease involvement in bone or viscera are allowed. Minimal metastatic disease is defined as: evidence of metastatic involvement as demonstrated by imaging only, not amenable to biopsy confirmation.
• Both men and women are allowed.
• The effects of ruxolitinib on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry until completion of chemotherapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document.
• LVEF > 50% calculated by echocardiogram (ECHO) or MUGA
• Patients may have bilateral breast cancer so long as one breast meets criteria for inflammatory breast cancer, and neither breast cancer has received prior therapy

Exclusion Criteria:

• Participants may not be receiving any other investigational agents.
• Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib.
• Participants receiving any medications or substances that are potent inhibitors of CYP3A4, including grapefruit juice are ineligible. Participants receiving fluconazole are also ineligible. (Please refer to Appendix B for the full list of potent inhibitors and washout periods).
• Chronic corticosteroid use in excess of the equivalent of prednisone 10 mg once daily.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because paclitaxel, doxorubicin, and cyclophosphamide have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated on study. These potential risks may also apply to other agents used in this study.
• Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
• Known HIV-positive individuals on combination antiretroviral therapy are eligible so long as they meet all other criteria. Known HIV-positive individuals who are not on combination antiretroviral therapy are not eligible because these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
• Clinically significant malabsorption syndrome.
• Patients may not have received paclitaxel, doxorubicin, or cyclophosphamide as anti-neoplastic therapy.
• Patients with prior radiation to the affected breast.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Paclitaxel (12weeks); Paclitaxel is administered weekly followed by standard Doxorubicin and Dyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively; 16 patients will be randomized from the Run-In 7 days of Ruxolitinib; The drug will be administered at a pre-determine dosage	Drug: Ruxolitinib; 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.; Other Names: Jakafi; Drug: Paclitaxel; 80 mg/m2, IV (in the vein) weekly for 12 weeks.; Other Names: Taxol; Drug: Doxorubicin; 60 mg/m2, IV (in the vein) every 14 days for 4 doses.; Other Names: Adriamycin; Drug: Cyclophosphamide; 600 mg/m2, IV (in the vein) every 14 days for 4 doses.; Other Names: Cytoxan
Experimental: Ruxolitinib with Paclitaxel (12weeks); Paclitaxel is administered with daily Ruxolitinib, followed by standard Doxorubicin and Cyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively; 16 patients will be randomized from the Run-In 7 days of Ruxolitinib; The drug will be administered at a pre-determine dosage	Drug: Ruxolitinib; 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.; Other Names: Jakafi; Drug: Paclitaxel; 80 mg/m2, IV (in the vein) weekly for 12 weeks.; Other Names: Taxol; Drug: Doxorubicin; 60 mg/m2, IV (in the vein) every 14 days for 4 doses.; Other Names: Adriamycin; Drug: Cyclophosphamide; 600 mg/m2, IV (in the vein) every 14 days for 4 doses.; Other Names: Cytoxan
Experimental: Ruxolitinib and Paclitaxel (12weeks); Paclitaxel is administered with daily Ruxolitinib, followed by standard Doxorubicin and Cyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively; 32 patients will be randomized from the Run-In 7 days of Ruxolitinib + Paclitaxel; The drug will be administered at a pre-determine dosage	Drug: Ruxolitinib; 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.; Other Names: Jakafi; Drug: Paclitaxel; 80 mg/m2, IV (in the vein) weekly for 12 weeks.; Other Names: Taxol; Drug: Doxorubicin; 60 mg/m2, IV (in the vein) every 14 days for 4 doses.; Other Names: Adriamycin; Drug: Cyclophosphamide; 600 mg/m2, IV (in the vein) every 14 days for 4 doses.; Other Names: Cytoxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	7 Days
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.	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.	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.	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.	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.	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.	28 weeks

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Collaborators: Incyte Corporation
• Investigators: Principal Investigator: Filipa Lynce, MD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Lynce F, Stevens LE, Li Z, Brock JE, Gulvady A, Huang Y, Nakhlis F, Patel A, Force JM, Haddad TC, Ueno N, Stearns V, Wolff AC, Clark AS, Bellon JR, Richardson ET, Balko JM, Krop IE, Winer EP, Lange P, Hwang ES, King TA, Tolaney SM, Thompson A, Gupta GP, Mittendorf EA, Regan MM, Overmoyer B, Polyak K. TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer. Breast Cancer Res. 2024 Jan 31;26(1):20. doi: 10.1186/s13058-024-01774-0.

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2018
• Primary Completion (Actual): December 31, 2022
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: August 9, 2016
• First Submitted That Met QC Criteria: August 22, 2016
• First Posted (Estimated): August 23, 2016

Study Record Updates

• Last Update Posted (Actual): February 4, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; Triple Negative Breast Cancer; Inflammatory Breast Cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Inflammatory Breast Neoplasms; Organic Chemicals; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Taxoids; Cyclodecanes; Diterpenes; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Anthracyclines; Naphthacenes; Aminoglycosides; Daunorubicin; Cyclophosphamide; Doxorubicin; Paclitaxel; ruxolitinib
• Other Study ID Numbers: 16-151

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No