Ruxolitinib Phosphate and Chemotherapy before Surgery in Treating Patients with Triple Negative Inflammatory Breast Cancer
This phase II trial studies how well ruxolitinib phosphate and chemotherapy before surgery work in treating patients with triple negative inflammatory breast cancer. Ruxolitinib phosphate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as paclitaxel, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ruxolitinib phosphate, paclitaxel, and chemotherapy before surgery may kill more tumor cells.
Inclusion Criteria
- Participants must have histologically confirmed invasive breast cancer; all histologic subtypes are eligible
- Patients must have known estrogen receptor (ER), progesterone receptor (PR), and HER2 status defined as triple-negative breast cancer (TNBC), defined as: * ER and PR =< 10% by immunohistochemistry, and HER2-negative (as per American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines, defined as immunohistochemistry [IHC] 0 or 1+, or fluorescence in situ hybridization [FISH] ratio < 2.0 or HER2 copy number < 6.0)
- Patients must have the clinical diagnosis of inflammatory breast cancer involving an intact breast
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Leukocytes >= 3,000/mm^3
- Absolute neutrophil count >= 1,500/mm^3
- Platelets >= 100,000/mm^3
- Bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (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 m^2 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
- 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
- Left ventricular ejection fraction (LVEF) >= 50% calculated by echocardiogram (ECHO) or multigated acquisition scan (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 or other agents used in this study
- Participants receiving any medications or substances that are potent inhibitors of CYP3A4, including grapefruit juice are ineligible; participants receiving fluconazole are also ineligible
- 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 human immunodeficiency virus (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 sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02876302.
PRIMARY OBJECTIVES:
I. To assess the effect of JAK inhibition with ruxolitinib phosphate (ruxolitinib) on phosphorylated (p)STAT3 level and STAT3 related gene expression by comparing molecular and genomic markers in pre-treatment biopsy specimens to post-ruxolitinib run-in biopsy specimens.
II. Changes in expression will be assessed on breast specimens exposed to single agent ruxolitinib and ruxolitinib combined with one dose of paclitaxel.
III. Assess the difference in pSTAT3 level and STAT3 related gene expression following exposure to ruxolitinib versus ruxolitinib with paclitaxel.
SECONDARY OBJECTIVES:
I. To determine pathologic complete response (pCR) rate after preoperative therapy.
II. To correlate effects on pSTAT3+ and STAT3 related gene expression with pCR: assess pSTAT3 level and STAT3 related gene expression on pre-treatment tumor biopsy specimens and to correlate expression with pCR.
III. To assess changes in pSTAT3 level and STAT3 related gene expression following either ruxolitinib or ruxolitinib with paclitaxel determined in tumor biopsy specimens and to correlate changes in expression with pCR.
IV. Assess difference in pCR rate following preoperative treatment with combination ruxolitinib with paclitaxel compared with paclitaxel alone.
V. To determine the efficacy of therapy defined as disease-free survival (DFS), time to treatment failure (TTF), and overall survival (OS).
VI. To assess the residual cancer burden (RCB) after preoperative therapy with combination ruxolitinib with paclitaxel or paclitaxel alone followed by doxorubicin/cyclophosphamide (AC) in triple negative inflammatory breast cancer.
VII. To assess any difference in RCB comparing preoperative combination ruxolitinib with paclitaxel compared with paclitaxel alone.
VIII. To describe changes in IL-6 and CRP plasma levels during treatment and to correlate pre-treatment IL-6 and CRP plasma levels with pCR and exposure to ruxolitinib, either alone or in combination with paclitaxel.
IX. To describe the distribution of CD44+/CD24- stem cell population in tumor pre- and post-exposure to ruxolitinib.
OUTLINE: Patients are randomized to 1 of 3 groups.
RUN-IN PHASE GROUP I: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on days -7 to -1.
RUN-IN PHASE GROUP II: Patients receive ruxolitinib phosphate as in Run-in Phase Group I.
RUN-IN PHASE GROUP III: Patients receive ruxolitinib phosphate as in Run-in Phase Group I. Patients also receive paclitaxel intravenously (IV) over 1 hour on day -7.
TREATMENT PHASE GROUP I: Patients receive paclitaxel IV over 1 hour once per week. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
TREATMENT PHASE GROUP II: Patients receive ruxolitinib phosphate PO BID on days 1-21 and paclitaxel IV over 1 hour once per week. Cycles repeat every 21 days for 12 weeks in the absence of disease progression or unacceptable toxicity.
TREATMENT PHASE GROUP III: Patients receive ruxolitinib phosphate and paclitaxel as in Treatment Phase Group II. Cycles repeat every 21 days for 11 weeks in the absence of disease progression or unacceptable toxicity.
All patients receive doxorubicin hydrochloride and cyclophosphamide IV over 2 hours once every 2 weeks. Cycles repeat every 2 weeks for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients who are not deemed surgical candidates may receive up to 2 additional doses of doxorubicin hydrochloride and cyclophosphamide every 2 or 3 weeks.
After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for up to 4 years, and then annually thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorFilipa Lynce
- Primary ID16-151
- Secondary IDsNCI-2017-00938
- ClinicalTrials.gov IDNCT02876302